302 results on '"Rowitch, David H."'
Search Results
2. Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination
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Kapell, Hannah, Fazio, Luca, Dyckow, Julia, Schwarz, Sophia, Cruz-Herranz, Andrés, Mayer, Christina, Campos, Joaquin, D´Este, Elisa, Möbius, Wiebke, Cordano, Christian, Pröbstel, Anne-Katrin, Gharagozloo, Marjan, Zulji, Amel, Naik, Venu Narayanan, Delank, Anna-Katharina, Cerina, Manuela, Müntefering, Thomas, Lerma-Martin, Celia, Sonner, Jana K, Sin, Jung H, Disse, Paul, Rychlik, Nicole, Sabeur, Khalida, Chavali, Manideep, Srivastava, Rajneesh, Heidenreich, Matthias, Fitzgerald, Kathryn C, Seebohm, Guiscard, Stadelmann, Christine, Hemmer, Bernhard, Platten, Michael, Jentsch, Thomas J, Engelhardt, Maren, Budde, Thomas, Nave, Klaus-Armin, Calabresi, Peter A, Friese, Manuel A, Green, Ari J, Acuna, Claudio, Rowitch, David H, Meuth, Sven G, and Schirmer, Lucas
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Neurosciences ,Brain Disorders ,Multiple Sclerosis ,Autoimmune Disease ,Neurodegenerative ,1.1 Normal biological development and functioning ,Underpinning research ,Neurological ,Mice ,Animals ,Humans ,Ranvier's Nodes ,Potassium ,Neurons ,Oligodendroglia ,Encephalomyelitis ,Autoimmune ,Experimental ,Inflammation ,Multiple sclerosis ,Neurodegeneration ,Neuroscience ,Potassium channels ,Medical and Health Sciences ,Immunology - Abstract
Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.
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- 2023
3. Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy
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Carapancea, Evelina, Cornet, Marie-Coralie, Milh, Mathieu, De Cosmo, Lucrezia, Huang, Eric J, Granata, Tiziana, Striano, Pasquale, Ceulemans, Berten, Stein, Anja, Morris-Rosendahl, Deborah, Conti, Greta, Mitra, Nipa, Raymond, F Lucy, Rowitch, David H, Solazzi, Roberta, Vercellino, Fabiana, De Liso, Paola, D'Onofrio, Gianluca, Boniver, Clementina, Danhaive, Olivier, Carkeek, Katherine, Salpietro, Vincenzo, Weckhuysen, Sarah, Fedrigo, Marny, Angelini, Annalisa, Castellotti, Barbara, Lederer, Damien, Benoit, Valerie, Raviglione, Federico, Guerrini, Renzo, Dilena, Robertino, and Cilio, Maria Roberta
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Paediatrics ,Biomedical and Clinical Sciences ,Neurosciences ,Perinatal Period - Conditions Originating in Perinatal Period ,Pediatric ,Clinical Research ,Brain Disorders ,Neurodegenerative ,Infant Mortality ,Neurological ,Humans ,Myoclonus ,Apnea ,Hyperekplexia ,Bradycardia ,Brain Diseases ,Seizures ,Phenotype ,Muscle Hypertonia ,Nuclear Proteins ,Clinical Sciences ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
Background and objectivesBRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.MethodsThrough a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.ResultsWe included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.DiscussionBRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.
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- 2023
4. Using Organoids to Model Sex Differences in the Human Brain
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Baron-Cohen, Simon, Allison, Carrie, Warrier, Varun, Tsompanidis, Alex, Adhya, Dwaipayan, Holt, Rosie, Smith, Paula, Parsons, Tracey, Davis, Joanna, Hassall, Matthew, Geschwind, Daniel H., Heazell, Alexander EP., Mill, Jonathan, Franklin, Alice, Bamford, Rosie, Davies, Jonathan, Hurles, Matthew E., Martin, Hilary C., Mousa, Mahmoud, Rowitch, David H., Niakan, Kathy K., Burton, Graham J., Ghafari, Fateneh, Srivastava, Deepak P., Dutan-Polit, Lucia, Pavlinek, Adam, Lancaster, Madeline A., Chiaradia, Ilaria, Biron-Shental, Tal, Gabis, Lidia V., Vernon, Anthony C., and Lancaster, Madeline
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- 2024
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5. Atypical Brain Aging and Its Association With Working Memory Performance in Major Depressive Disorder
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Adamson, Chris, Adler, Sophie, Alexander-Bloch, Aaron F., Anagnostou, Evdokia, Anderson, Kevin M., Areces-Gonzalez, Ariosky, Astle, Duncan E., Auyeung, Bonnie, Ayub, Muhammad, Bae, Jong Bin, Ball, Gareth, Baron-Cohen, Simon, Beare, Richard, Bedford, Saashi A., Benegal, Vivek, Bethlehem, Richard A.I., Beyer, Frauke, Blangero, John, Cábez, Manuel Blesa, Boardman, James P., Borzage, Matthew, Bosch-Bayard, Jorge F., Bourke, Niall, Bullmore, Edward T., Calhoun, Vince D., Chakravarty, Mallar M., Chen, Christina, Chertavian, Casey, Chetelat, Gaël, Chong, Yap S., Corvin, Aiden, Costantino, Manuela, Courchesne, Eric, Crivello, Fabrice, Cropley, Vanessa L., Crosbie, Jennifer, Crossley, Nicolas, Delarue, Marion, Delorme, Richard, Desrivieres, Sylvane, Devenyi, Gabriel, Di Biase, Maria A., Dolan, Ray, Donald, Kirsten A., Donohoe, Gary, Dorfschmidt, Lena, Dunlop, Katharine, Edwards, Anthony D., Elison, Jed T., Ellis, Cameron T., Elman, Jeremy A., Eyler, Lisa, Fair, Damien A., Fletcher, Paul C., Fonagy, Peter, Franz, Carol E., Galan-Garcia, Lidice, Gholipour, Ali, Giedd, Jay, Gilmore, John H., Glahn, David C., Goodyer, Ian M., Grant, P.E., Groenewold, Nynke A., Gudapati, Shreya, Gunning, Faith M., Gur, Raquel E., Gur, Ruben C., Hammill, Christopher F., Hansson, Oskar, Hedden, Trey, Heinz, Andreas, Henson, Richard N., Heuer, Katja, Hoare, Jacqueline, Holla, Bharath, Holmes, Avram J., Huang, Hao, Ipser, Jonathan, Jack, Clifford R., Jr., Jackowski, Andrea P., Jia, Tianye, Jones, David T., Jones, Peter B., Kahn, Rene S., Karlsson, Hasse, Karlsson, Linnea, Kawashima, Ryuta, Kelley, Elizabeth A., Kern, Silke, Kim, Ki-Woong, Kitzbichler, Manfred G., Kremen, William S., Lalonde, François, Landeau, Brigitte, Lerch, Jason, Lewis, John D., Li, Jiao, Liao, Wei, Liston, Conor, Lombardo, Michael V., Lv, Jinglei, Mallard, Travis T., Marcelis, Machteld, Mathias, Samuel R., Mazoyer, Bernard, McGuire, Philip, Meaney, Michael J., Mechelli, Andrea, Misic, Bratislav, Morgan, Sarah E., Mothersill, David, Ortinau, Cynthia, Ossenkoppele, Rik, Ouyang, Minhui, Palaniyappan, Lena, Paly, Leo, Pan, Pedro M., Pantelis, Christos, Park, Min Tae M., Paus, Tomas, Pausova, Zdenka, Paz-Linares, Deirel, Binette, Alexa Pichet, Pierce, Karen, Qian, Xing, Qiu, Anqi, Raznahan, Armin, Rittman, Timothy, Rodrigue, Amanda, Rollins, Caitlin K., Romero-Garcia, Rafael, Ronan, Lisa, Rosenberg, Monica D., Rowitch, David H., Salum, Giovanni A., Satterthwaite, Theodore D., Schaare, H. Lina, Schabdach, Jenna, Schachar, Russell J., Schöll, Michael, Schultz, Aaron P., Seidlitz, Jakob, Sharp, David, Shinohara, Russell T., Skoog, Ingmar, Smyser, Christopher D., Sperling, Reisa A., Stein, Dan J., Stolicyn, Aleks, Suckling, John, Sullivan, Gemma, Thyreau, Benjamin, Toro, Roberto, Traut, Nicolas, Tsvetanov, Kamen A., Turk-Browne, Nicholas B., Tuulari, Jetro J., Tzourio, Christophe, Vachon-Presseau, Étienne, Valdes-Sosa, Mitchell J., Valdes-Sosa, Pedro A., Valk, Sofie L., van Amelsvoort, Therese, Vandekar, Simon N., Vasung, Lana, Vértes, Petra E., Victoria, Lindsay W., Villeneuve, Sylvia, Villringer, Arno, Vogel, Jacob W., Wagstyl, Konrad, Wang, Yin-Shan S., Warfield, Simon K., Warrier, Varun, Westman, Eric, Westwater, Margaret L., Whalley, Heather C., White, Simon R., Witte, A. Veronica, Yang, Ning, Yeo, B.T. Thomas, Yun, Hyuk Jin, Zalesky, Andrew, Zar, Heather J., Zettergren, Anna, Zhou, Juan H., Ziauddeen, Hisham, Zimmerman, Dabriel, Zugman, Andre, Zuo, Xi-Nian N., Ho, Natalie C.W., Nogovitsyn, Nikita, Metzak, Paul, Ballester, Pedro L., Hassel, Stefanie, Rotzinger, Susan, Poppenk, Jordan, Lam, Raymond W., Taylor, Valerie H., Milev, Roumen, Frey, Benicio N., Harkness, Kate L., Addington, Jean, and Kennedy, Sidney H.
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- 2024
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6. A retroviral link to vertebrate myelination through retrotransposon-RNA-mediated control of myelin gene expression
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Ghosh, Tanay, Almeida, Rafael G., Zhao, Chao, Mannioui, Abdelkrim, Martin, Elodie, Fleet, Alex, Chen, Civia Z., Assinck, Peggy, Ellams, Sophie, Gonzalez, Ginez A., Graham, Stephen C., Rowitch, David H., Stott, Katherine, Adams, Ian, Zalc, Bernard, Goldman, Nick, Lyons, David A., and Franklin, Robin J.M.
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- 2024
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7. Evidence for glutamine synthetase function in mouse spinal cord oligodendrocytes
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Haim, Lucile Ben, Schirmer, Lucas, Zulji, Amel, Sabeur, Khalida, Tiret, Brice, Ribon, Matthieu, Chang, Sandra, Lamers, Wouter H, Boillée, Séverine, Chaumeil, Myriam M, and Rowitch, David H
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Neurodegenerative ,Stem Cell Research ,Multiple Sclerosis ,Autoimmune Disease ,Neurosciences ,Brain Disorders ,Genetics ,Neurological ,Amyotrophic Lateral Sclerosis ,Animals ,Disease Models ,Animal ,Glutamate-Ammonia Ligase ,Humans ,Mice ,Mice ,Transgenic ,Motor Neurons ,Oligodendroglia ,Spinal Cord ,Superoxide Dismutase ,amyotrophic lateral sclerosis ,glutamine synthetase ,motor neurons ,oligodendrocytes ,peak strength ,spinal cord ,Neurology & Neurosurgery - Abstract
Glutamine synthetase (GS) is a key enzyme that metabolizes glutamate into glutamine. While GS is highly enriched in astrocytes, expression in other glial lineages has been noted. Using a combination of reporter mice and cell type-specific markers, we show that GS is expressed in myelinating oligodendrocytes (OL) but not oligodendrocyte progenitor cells of the mouse and human ventral spinal cord. To investigate the role of GS in mature OL, we used a conditional knockout (cKO) approach to selectively delete GS-encoding gene (Glul) in OL, which caused a significant decrease in glutamine levels on mouse spinal cord extracts. GS cKO mice (CNP-cre+ :Glulfl/fl ) showed no differences in motor neuron numbers, size or axon density; OL differentiation and myelination in the ventral spinal cord was normal up to 6 months of age. Interestingly, GS cKO mice showed a transient and specific decrease in peak force while locomotion and motor coordination remained unaffected. Last, GS expression in OL was increased in chronic pathological conditions in both mouse and humans. We found a disease-stage dependent increase of OL expressing GS in the ventral spinal cord of SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Moreover, we showed that GLUL transcripts levels were increased in OL in leukocortical tissue from multiple sclerosis but not control patients. These findings provide evidence towards OL-encoded GS function in spinal cord sensorimotor axis, which is dysregulated in chronic neurological diseases.
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- 2021
8. Neuroprotective effects of Sonic hedgehog agonist SAG in a rat model of neonatal stroke
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Nguyen, Vien, Chavali, Manideep, Larpthaveesarp, Amara, Kodali, Srikirti, Gonzalez, Ginez, Franklin, Robin JM, Rowitch, David H, and Gonzalez, Fernando
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Brain Disorders ,Stem Cell Research ,Pediatric ,Stem Cell Research - Nonembryonic - Non-Human ,Stroke ,Neurosciences ,Neurological ,Animals ,Behavior ,Animal ,Cell Proliferation ,Disease Models ,Animal ,Hedgehog Proteins ,Humans ,Infant ,Newborn ,Infarction ,Middle Cerebral Artery ,Mice ,Neuroprotective Agents ,Rats ,Rats ,Sprague-Dawley ,Small Molecule Libraries ,Paediatrics and Reproductive Medicine ,Public Health and Health Services ,Pediatrics - Abstract
BackgroundNeonatal stroke affects 1 in 2800 live births and is a major cause of neurological injury. The Sonic hedgehog (Shh) signaling pathway is critical for central nervous system (CNS) development and has neuroprotective and reparative effects in different CNS injury models. Previous studies have demonstrated beneficial effects of small molecule Shh-Smoothened agonist (SAG) against neonatal cerebellar injury and it improves Down syndrome-related brain structural deficits in mice. Here we investigated SAG neuroprotection in rat models of neonatal ischemia-reperfusion (stroke) and adult focal white matter injury.MethodsWe used transient middle cerebral artery occlusion at P10 and ethidium bromide (EB) injection in adult rats to induce damage. Following surgery and SAG or vehicle treatment, we analyzed tissue loss, cell proliferation and fate, and behavioral outcome.ResultsWe report that a single dose of SAG administered following neonatal stroke preserved brain volume, reduced gliosis, enhanced oligodendrocyte progenitor cell (OPC) and EC proliferation, and resulted in long-term cognitive improvement. Single-dose SAG also promoted proliferation of OPCs following focal demyelination in the adult rat.ConclusionsThese findings indicate benefit of one-time SAG treatment post insult in reducing brain injury and improving behavioral outcome after experimental neonatal stroke.ImpactA one-time dose of small molecule Sonic hedgehog agonist protected against neonatal stroke and improved long-term behavioral outcomes in a rat model. This study extends the use of Sonic hedgehog in treating developing brain injury, previously shown in animal models of Down syndrome and cerebellar injury. Sonic hedgehog agonist is one of the most promising therapies in treating neonatal stroke thanks to its safety profile and low dosage.
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- 2021
9. Reactive astrocyte nomenclature, definitions, and future directions
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Escartin, Carole, Galea, Elena, Lakatos, András, O’Callaghan, James P, Petzold, Gabor C, Serrano-Pozo, Alberto, Steinhäuser, Christian, Volterra, Andrea, Carmignoto, Giorgio, Agarwal, Amit, Allen, Nicola J, Araque, Alfonso, Barbeito, Luis, Barzilai, Ari, Bergles, Dwight E, Bonvento, Gilles, Butt, Arthur M, Chen, Wei-Ting, Cohen-Salmon, Martine, Cunningham, Colm, Deneen, Benjamin, De Strooper, Bart, Díaz-Castro, Blanca, Farina, Cinthia, Freeman, Marc, Gallo, Vittorio, Goldman, James E, Goldman, Steven A, Götz, Magdalena, Gutiérrez, Antonia, Haydon, Philip G, Heiland, Dieter H, Hol, Elly M, Holt, Matthew G, Iino, Masamitsu, Kastanenka, Ksenia V, Kettenmann, Helmut, Khakh, Baljit S, Koizumi, Schuichi, Lee, C Justin, Liddelow, Shane A, MacVicar, Brian A, Magistretti, Pierre, Messing, Albee, Mishra, Anusha, Molofsky, Anna V, Murai, Keith K, Norris, Christopher M, Okada, Seiji, Oliet, Stéphane HR, Oliveira, João F, Panatier, Aude, Parpura, Vladimir, Pekna, Marcela, Pekny, Milos, Pellerin, Luc, Perea, Gertrudis, Pérez-Nievas, Beatriz G, Pfrieger, Frank W, Poskanzer, Kira E, Quintana, Francisco J, Ransohoff, Richard M, Riquelme-Perez, Miriam, Robel, Stefanie, Rose, Christine R, Rothstein, Jeffrey D, Rouach, Nathalie, Rowitch, David H, Semyanov, Alexey, Sirko, Swetlana, Sontheimer, Harald, Swanson, Raymond A, Vitorica, Javier, Wanner, Ina-Beate, Wood, Levi B, Wu, Jiaqian, Zheng, Binhai, Zimmer, Eduardo R, Zorec, Robert, Sofroniew, Michael V, and Verkhratsky, Alexei
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Neurosciences ,Brain Disorders ,Neurological ,Aging ,Animals ,Astrocytes ,Brain ,Brain Diseases ,Brain Injuries ,Humans ,Spinal Cord ,Spinal Cord Injuries ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.
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- 2021
10. Origins and Proliferative States of Human Oligodendrocyte Precursor Cells.
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Huang, Wei, Bhaduri, Aparna, Velmeshev, Dmitry, Wang, Shaohui, Wang, Li, Rottkamp, Catherine A, Alvarez-Buylla, Arturo, Rowitch, David H, and Kriegstein, Arnold R
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Cerebral Cortex ,Cells ,Cultured ,Humans ,Cadherins ,RNA ,Small Interfering ,Immunohistochemistry ,Cell Proliferation ,Neurogenesis ,HEK293 Cells ,Single-Cell Analysis ,Ependymoglial Cells ,White Matter ,ErbB Receptors ,Cadherin Related Proteins ,Oligodendrocyte Precursor Cells ,RNA-Seq ,EGFR ,OPC ,PCDH15 ,cortical expansion ,oligodendrogenesis ,self-repulsion ,Neurosciences ,Regenerative Medicine ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,1.1 Normal biological development and functioning ,Underpinning research ,Neurological ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Human cerebral cortex size and complexity has increased greatly during evolution. While increased progenitor diversity and enhanced proliferative potential play important roles in human neurogenesis and gray matter expansion, the mechanisms of human oligodendrogenesis and white matter expansion remain largely unknown. Here, we identify EGFR-expressing "Pre-OPCs" that originate from outer radial glial cells (oRGs) and undergo mitotic somal translocation (MST) during division. oRG-derived Pre-OPCs provide an additional source of human cortical oligodendrocyte precursor cells (OPCs) and define a lineage trajectory. We further show that human OPCs undergo consecutive symmetric divisions to exponentially increase the progenitor pool size. Additionally, we find that the OPC-enriched gene, PCDH15, mediates daughter cell repulsion and facilitates proliferation. These findings indicate properties of OPC derivation, proliferation, and dispersion important for human white matter expansion and myelination.
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- 2020
11. Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map
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Bayraktar, Omer Ali, Bartels, Theresa, Holmqvist, Staffan, Kleshchevnikov, Vitalii, Martirosyan, Araks, Polioudakis, Damon, Ben Haim, Lucile, Young, Adam MH, Batiuk, Mykhailo Y, Prakash, Kirti, Brown, Alexander, Roberts, Kenny, Paredes, Mercedes F, Kawaguchi, Riki, Stockley, John H, Sabeur, Khalida, Chang, Sandra M, Huang, Eric, Hutchinson, Peter, Ullian, Erik M, Hemberg, Martin, Coppola, Giovanni, Holt, Matthew G, Geschwind, Daniel H, and Rowitch, David H
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Biomedical and Clinical Sciences ,Neurosciences ,Genetics ,Biotechnology ,Brain Disorders ,Human Genome ,1.1 Normal biological development and functioning ,Underpinning research ,Neurological ,Animals ,Astrocytes ,Brain Mapping ,Cerebral Cortex ,Humans ,Mice ,Neurons ,Transcriptome ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Although the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. In the present study, we developed a high-content pipeline, the large-area spatial transcriptomic (LaST) map, which can quantify single-cell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.
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- 2020
12. Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation
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Nobuta, Hiroko, Yang, Nan, Ng, Yi Han, Marro, Samuele G, Sabeur, Khalida, Chavali, Manideep, Stockley, John H, Killilea, David W, Walter, Patrick B, Zhao, Chao, Huie, Philip, Goldman, Steven A, Kriegstein, Arnold R, Franklin, Robin JM, Rowitch, David H, and Wernig, Marius
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Autoimmune Disease ,Neurosciences ,Multiple Sclerosis ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Stem Cell Research - Embryonic - Human ,Stem Cell Research ,Genetics ,Neurodegenerative ,Rare Diseases ,Brain Disorders ,Stem Cell Research - Induced Pluripotent Stem Cell ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Cell Differentiation ,Cells ,Cultured ,Deferiprone ,Ferroptosis ,Humans ,Induced Pluripotent Stem Cells ,Iron ,Iron Chelating Agents ,Lipid Peroxidation ,Mice ,Mice ,Mutant Strains ,Mutation ,Myelin Proteolipid Protein ,Oligodendroglia ,Pelizaeus-Merzbacher Disease ,Stem Cell Transplantation ,Targeted Gene Repair ,ferroptosis ,gene correction ,induced pluripotent stem cells ,iron chelation ,leukodystrophy ,myelination ,oligodendrocyte ,patient models ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescued mutant oligodendrocyte apoptosis, survival, and differentiationin vitro, and post-transplantation in vivo. Finally, systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation. Thus, oligodendrocyte iron-induced cell death and myelination is rescued by iron chelation in PMD pre-clinical models.
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- 2019
13. Genetic correlates of phenotypic heterogeneity in autism
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Warrier, Varun, Zhang, Xinhe, Reed, Patrick, Havdahl, Alexandra, Moore, Tyler M., Cliquet, Freddy, Leblond, Claire S., Rolland, Thomas, Rosengren, Anders, Rowitch, David H., Hurles, Matthew E., Geschwind, Daniel H., Børglum, Anders D., Robinson, Elise B., Grove, Jakob, Martin, Hilary C., Bourgeron, Thomas, and Baron-Cohen, Simon
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- 2022
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14. Atypical brain aging and its association with working memory performance in major depressive disorder
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Ho, Natalie C.W., primary, Bethlehem, Richard AI., additional, Seidlitz, Jakob, additional, Nogovitsyn, Nikita, additional, Metzak, Paul, additional, Ballester, Pedro L., additional, Hassel, Stefanie, additional, Rotzinger, Susan, additional, Poppenk, Jordan, additional, Lam, Raymond W., additional, Taylor, Valerie H., additional, Milev, Roumen, additional, Adamson, Chris, additional, Adler, Sophie, additional, Alexander-Bloch, Aaron F., additional, Anagnostou, Evdokia, additional, Anderson, Kevin M., additional, Areces-Gonzalez, Ariosky, additional, Astle, Duncan E., additional, Auyeung, Bonnie, additional, Ayub, Muhammad, additional, Bae, Jong Bin, additional, Ball, Gareth, additional, Baron-Cohen, Simon, additional, Beare, Richard, additional, Bedford, Saashi A., additional, Benegal, Vivek, additional, Bethlehem, Richard A.I., additional, Beyer, Frauke, additional, Blangero, John, additional, Blesa Cábez, Manuel, additional, Boardman, James P., additional, Borzage, Matthew, additional, Bosch-Bayard, Jorge F., additional, Bourke, Niall, additional, Bullmore, Edward T., additional, Calhoun, Vince D., additional, Chakravarty, Mallar M., additional, Chen, Christina, additional, Chertavian, Casey, additional, Chetelat, Gaël, additional, Chong, Yap S., additional, Corvin, Aiden, additional, Costantino, Manuela, additional, Courchesne, Eric, additional, Crivello, Fabrice, additional, Cropley, Vanessa L., additional, Crosbie, Jennifer, additional, Crossley, Nicolas, additional, Delarue, Marion, additional, Delorme, Richard, additional, Desrivieres, Sylvane, additional, Devenyi, Gabriel, additional, Di Biase, Maria A., additional, Dolan, Ray, additional, Donald, Kirsten A., additional, Donohoe, Gary, additional, Dorfschmidt, Lena, additional, Dunlop, Katharine, additional, Edwards, Anthony D., additional, Elison, Jed T., additional, Ellis, Cameron T., additional, Elman, Jeremy A., additional, Eyler, Lisa, additional, Fair, Damien A., additional, Fletcher, Paul C., additional, Fonagy, Peter, additional, Franz, Carol E., additional, Galan-Garcia, Lidice, additional, Gholipour, Ali, additional, Giedd, Jay, additional, Gilmore, John H., additional, Glahn, David C., additional, Goodyer, Ian M., additional, Grant, P.E., additional, Groenewold, Nynke A., additional, Gudapati, Shreya, additional, Gunning, Faith M., additional, Gur, Raquel E., additional, Gur, Ruben C., additional, Hammill, Christopher F., additional, Hansson, Oskar, additional, Hedden, Trey, additional, Heinz, Andreas, additional, Henson, Richard N., additional, Heuer, Katja, additional, Hoare, Jacqueline, additional, Holla, Bharath, additional, Holmes, Avram J., additional, Huang, Hao, additional, Ipser, Jonathan, additional, Jack, Clifford R., additional, Jackowski, Andrea P., additional, Jia, Tianye, additional, Jones, David T., additional, Jones, Peter B., additional, Kahn, Rene S., additional, Karlsson, Hasse, additional, Karlsson, Linnea, additional, Kawashima, Ryuta, additional, Kelley, Elizabeth A., additional, Kern, Silke, additional, Kim, Ki-Woong, additional, Kitzbichler, Manfred G., additional, Kremen, William S., additional, Lalonde, François, additional, Landeau, Brigitte, additional, Lerch, Jason, additional, Lewis, John D., additional, Li, Jiao, additional, Liao, Wei, additional, Liston, Conor, additional, Lombardo, Michael V., additional, Lv, Jinglei, additional, Mallard, Travis T., additional, Marcelis, Machteld, additional, Mathias, Samuel R., additional, Mazoyer, Bernard, additional, McGuire, Philip, additional, Meaney, Michael J., additional, Mechelli, Andrea, additional, Misic, Bratislav, additional, Morgan, Sarah E., additional, Mothersill, David, additional, Ortinau, Cynthia, additional, Ossenkoppele, Rik, additional, Ouyang, Minhui, additional, Palaniyappan, Lena, additional, Paly, Leo, additional, Pan, Pedro M., additional, Pantelis, Christos, additional, Park, Min Tae M., additional, Paus, Tomas, additional, Pausova, Zdenka, additional, Paz-Linares, Deirel, additional, Pichet Binette, Alexa, additional, Pierce, Karen, additional, Qian, Xing, additional, Qiu, Anqi, additional, Raznahan, Armin, additional, Rittman, Timothy, additional, Rodrigue, Amanda, additional, Rollins, Caitlin K., additional, Romero-Garcia, Rafael, additional, Ronan, Lisa, additional, Rosenberg, Monica D., additional, Rowitch, David H., additional, Salum, Giovanni A., additional, Satterthwaite, Theodore D., additional, Schaare, H. Lina, additional, Schabdach, Jenna, additional, Schachar, Russell J., additional, Schöll, Michael, additional, Schultz, Aaron P., additional, Sharp, David, additional, Shinohara, Russell T., additional, Skoog, Ingmar, additional, Smyser, Christopher D., additional, Sperling, Reisa A., additional, Stein, Dan J., additional, Stolicyn, Aleks, additional, Suckling, John, additional, Sullivan, Gemma, additional, Thyreau, Benjamin, additional, Toro, Roberto, additional, Traut, Nicolas, additional, Tsvetanov, Kamen A., additional, Turk-Browne, Nicholas B., additional, Tuulari, Jetro J., additional, Tzourio, Christophe, additional, Vachon-Presseau, Étienne, additional, Valdes-Sosa, Mitchell J., additional, Valdes-Sosa, Pedro A., additional, Valk, Sofie L., additional, van Amelsvoort, Therese, additional, Vandekar, Simon N., additional, Vasung, Lana, additional, Vértes, Petra E., additional, Victoria, Lindsay W., additional, Villeneuve, Sylvia, additional, Villringer, Arno, additional, Vogel, Jacob W., additional, Wagstyl, Konrad, additional, Wang, Yin-Shan S., additional, Warfield, Simon K., additional, Warrier, Varun, additional, Westman, Eric, additional, Westwater, Margaret L., additional, Whalley, Heather C., additional, White, Simon R., additional, Witte, A. Veronica, additional, Yang, Ning, additional, Yeo, B.T. Thomas, additional, Yun, Hyuk Jin, additional, Zalesky, Andrew, additional, Zar, Heather J., additional, Zettergren, Anna, additional, Zhou, Juan H., additional, Ziauddeen, Hisham, additional, Zimmerman, Dabriel, additional, Zugman, Andre, additional, Zuo, Xi-Nian N., additional, Frey, Benicio N., additional, Harkness, Kate L., additional, Addington, Jean, additional, and Kennedy, Sidney H., additional
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- 2024
- Full Text
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15. Neuronal vulnerability and multilineage diversity in multiple sclerosis
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Schirmer, Lucas, Velmeshev, Dmitry, Holmqvist, Staffan, Kaufmann, Max, Werneburg, Sebastian, Jung, Diane, Vistnes, Stephanie, Stockley, John H, Young, Adam, Steindel, Maike, Tung, Brian, Goyal, Nitasha, Bhaduri, Aparna, Mayer, Simone, Engler, Jan Broder, Bayraktar, Omer A, Franklin, Robin JM, Haeussler, Maximilian, Reynolds, Richard, Schafer, Dorothy P, Friese, Manuel A, Shiow, Lawrence R, Kriegstein, Arnold R, and Rowitch, David H
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Autoimmune Disease ,Human Genome ,Multiple Sclerosis ,Brain Disorders ,Neurosciences ,Genetics ,Neurodegenerative ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adult ,Animals ,Astrocytes ,Autopsy ,Cell Lineage ,Cryopreservation ,Female ,Homeodomain Proteins ,Humans ,Macrophages ,Male ,Mice ,Microglia ,Middle Aged ,Myelin Sheath ,Neurons ,Oligodendroglia ,Phagocytosis ,RNA ,Small Nuclear ,RNA-Seq ,Transcriptome ,General Science & Technology - Abstract
Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.
- Published
- 2019
16. Long-Term Safety, Immunologic Response, and Imaging Outcomes following Neural Stem Cell Transplantation for Pelizaeus-Merzbacher Disease
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Gupta, Nalin, Henry, Roland G, Kang, Sang-Mo, Strober, Jonathan, Lim, Daniel A, Ryan, Tamara, Perry, Rachel, Farrell, Jody, Ulman, Mary, Rajalingam, Raja, Gage, Allyson, Huhn, Stephen L, Barkovich, A James, and Rowitch, David H
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Clinical Research ,Clinical Trials and Supportive Activities ,Transplantation ,Brain Disorders ,Neurosciences ,Regenerative Medicine ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research ,Biomedical Imaging ,Neurological ,Brain ,Child ,Preschool ,Follow-Up Studies ,HLA Antigens ,Humans ,Infant ,Isoantibodies ,Magnetic Resonance Imaging ,Male ,Neural Stem Cells ,Pelizaeus-Merzbacher Disease ,Severity of Illness Index ,Stem Cell Transplantation ,Transplantation ,Homologous ,Treatment Outcome ,Pelizaeus-Merzbacher disease ,leukodystrophy ,myelin ,neural stem cells ,neurodegenerative disease ,oligodendrocyte ,pediatric ,transplantation ,Biochemistry and Cell Biology ,Clinical Sciences - Abstract
Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. At year 2, all subjects exhibited diffusion MRI changes at the implantation sites as well as in more distant brain regions. There were persistent, increased signal changes in the three patients who were studied up to year 5. Two of four subjects developed donor-specific HLA alloantibodies, demonstrating that neural stem cells can elicit an immune response when injected into the CNS, and suggesting the importance of monitoring immunologic parameters and identifying markers of engraftment in future studies.
- Published
- 2019
17. Single-cell genomics identifies cell type–specific molecular changes in autism
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Velmeshev, Dmitry, Schirmer, Lucas, Jung, Diane, Haeussler, Maximilian, Perez, Yonatan, Mayer, Simone, Bhaduri, Aparna, Goyal, Nitasha, Rowitch, David H, and Kriegstein, Arnold R
- Subjects
Mental Health ,Brain Disorders ,Human Genome ,Pediatric ,Genetics ,Autism ,Neurosciences ,Behavioral and Social Science ,Intellectual and Developmental Disabilities (IDD) ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adolescent ,Autistic Disorder ,Cell Nucleus ,Child ,Child ,Preschool ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Genomics ,Humans ,Male ,Microglia ,Neocortex ,Neurons ,Sequence Analysis ,RNA ,Single-Cell Analysis ,Young Adult ,General Science & Technology - Abstract
Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.
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- 2019
18. Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis
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Pla, Ramon, Stanco, Amelia, Howard, MacKenzie A, Rubin, Anna N, Vogt, Daniel, Mortimer, Niall, Cobos, Inma, Potter, Gregory Brian, Lindtner, Susan, Price, James D, Nord, Alex S, Visel, Axel, Schreiner, Christoph E, Baraban, Scott C, Rowitch, David H, and Rubenstein, John LR
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Biomedical and Clinical Sciences ,Neurosciences ,Genetics ,Pediatric ,Mental Health ,2.1 Biological and endogenous factors ,Animals ,Cerebral Cortex ,Female ,GABAergic Neurons ,Gene Expression Regulation ,Developmental ,Glutamate Decarboxylase ,Homeodomain Proteins ,Interneurons ,Male ,Mice ,Knockout ,Miniature Postsynaptic Potentials ,Synapses ,Transcription Factors ,Vesicular Inhibitory Amino Acid Transport Proteins ,gamma-Aminobutyric Acid ,cortex ,Dlx ,Gad ,interneuron ,synapse ,Psychology ,Cognitive Sciences ,Experimental Psychology ,Biological psychology ,Cognitive and computational psychology - Abstract
The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.
- Published
- 2018
19. Neuroinflammatory reactive astrocyte formation correlates with adverse outcomes in perinatal white matter injury.
- Author
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Renz, Patricia, Steinfort, Marel, Haesler, Valérie, Tscherrig, Vera, Huang, Eric J., Chavali, Manideep, Liddelow, Shane, Rowitch, David H., Surbek, Daniel, Schoeberlein, Andreina, and Brosius Lutz, Amanda
- Published
- 2024
- Full Text
- View/download PDF
20. Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity.
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Schirmer, Lucas, Möbius, Wiebke, Zhao, Chao, Cruz-Herranz, Andrés, Ben Haim, Lucile, Cordano, Christian, Shiow, Lawrence R, Kelley, Kevin W, Sadowski, Boguslawa, Timmons, Garrett, Pröbstel, Anne-Katrin, Wright, Jackie N, Sin, Jung Hyung, Devereux, Michael, Morrison, Daniel E, Chang, Sandra M, Sabeur, Khalida, Green, Ari J, Nave, Klaus-Armin, Franklin, Robin Jm, and Rowitch, David H
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Spinal Cord ,Neuroglia ,Oligodendroglia ,Neurons ,Axons ,Animals ,Mice ,Knockout ,Humans ,Mice ,Seizures ,Potassium Channels ,Inwardly Rectifying ,Leukoencephalopathies ,Kir4.1 ,mouse ,neurobiology ,neurodegeneration ,neuroscience ,oligodendrocytes ,visual System ,white matter ,Knockout ,Potassium Channels ,Inwardly Rectifying ,Biochemistry and Cell Biology - Abstract
Glial support is critical for normal axon function and can become dysregulated in white matter (WM) disease. In humans, loss-of-function mutations of KCNJ10, which encodes the inward-rectifying potassium channel KIR4.1, causes seizures and progressive neurological decline. We investigated Kir4.1 functions in oligodendrocytes (OLs) during development, adulthood and after WM injury. We observed that Kir4.1 channels localized to perinodal areas and the inner myelin tongue, suggesting roles in juxta-axonal K+ removal. Conditional knockout (cKO) of OL-Kcnj10 resulted in late onset mitochondrial damage and axonal degeneration. This was accompanied by neuronal loss and neuro-axonal dysfunction in adult OL-Kcnj10 cKO mice as shown by delayed visual evoked potentials, inner retinal thinning and progressive motor deficits. Axon pathologies in OL-Kcnj10 cKO were exacerbated after WM injury in the spinal cord. Our findings point towards a critical role of OL-Kir4.1 for long-term maintenance of axonal function and integrity during adulthood and after WM injury.
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- 2018
21. A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment
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Griveau, Amelie, Seano, Giorgio, Shelton, Samuel J, Kupp, Robert, Jahangiri, Arman, Obernier, Kirsten, Krishnan, Shanmugarajan, Lindberg, Olle R, Yuen, Tracy J, Tien, An-Chi, Sabo, Jennifer K, Wang, Nancy, Chen, Ivy, Kloepper, Jonas, Larrouquere, Louis, Ghosh, Mitrajit, Tirosh, Itay, Huillard, Emmanuelle, Alvarez-Buylla, Arturo, Oldham, Michael C, Persson, Anders I, Weiss, William A, Batchelor, Tracy T, Stemmer-Rachamimov, Anat, Suvà, Mario L, Phillips, Joanna J, Aghi, Manish K, Mehta, Shwetal, Jain, Rakesh K, and Rowitch, David H
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Neurosciences ,Rare Diseases ,Cancer ,Brain Cancer ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Bevacizumab ,Blood-Brain Barrier ,Brain Neoplasms ,Cell Line ,Tumor ,Gene Expression Regulation ,Neoplastic ,Glioma ,Humans ,Mice ,Neoplasm Transplantation ,Oligodendrocyte Transcription Factor 2 ,Oligodendroglia ,Temozolomide ,Tumor Cells ,Cultured ,Tumor Microenvironment ,Wnt Proteins ,Wnt Signaling Pathway ,Olig2 ,Wnt ,angiogenesis ,astrocyte ,blood-brain barrier ,glioma ,invasiveness ,oligodendrocyte precursor ,p53 ,vessel co-option ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions.
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- 2018
22. Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength.
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Kelley, Kevin W, Ben Haim, Lucile, Schirmer, Lucas, Tyzack, Giulia E, Tolman, Michaela, Miller, John G, Tsai, Hui-Hsin, Chang, Sandra M, Molofsky, Anna V, Yang, Yongjie, Patani, Rickie, Lakatos, Andras, Ullian, Erik M, and Rowitch, David H
- Subjects
Astrocytes ,Motor Neurons ,Cells ,Cultured ,Animals ,Animals ,Newborn ,Mice ,Transgenic ,Humans ,Mice ,Amyotrophic Lateral Sclerosis ,Potassium Channels ,Inwardly Rectifying ,Organ Culture Techniques ,Female ,Male ,Induced Pluripotent Stem Cells ,Kir4.1 ,amyotrophic lateral sclerosis ,astrocyte diversity ,fast-twitch muscle ,motor neuron ,neurodegeneration ,peak strength ,spinal cord development ,Cells ,Cultured ,Newborn ,Transgenic ,Potassium Channels ,Inwardly Rectifying ,Neurosciences ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast α-motor neurons (FαMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report that ventral horn astrocytes express the inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) around MNs in a VGLUT1-dependent manner. Loss of astrocyte-encoded Kir4.1 selectively altered FαMN size and function and led to reduced peak strength. Overexpression of Kir4.1 in astrocytes was sufficient to increase MN size through activation of the PI3K/mTOR/pS6 pathway. Kir4.1 was downregulated cell autonomously in astrocytes derived from amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation. However, astrocyte Kir4.1 was dispensable for FαMN survival even in the mutant SOD1 background. These findings show that astrocyte Kir4.1 is essential for maintenance of peak strength and suggest that Kir4.1 downregulation might uncouple symptoms of muscle weakness from MN cell death in diseases like ALS.
- Published
- 2018
23. Systematic Three-Dimensional Coculture Rapidly Recapitulates Interactions between Human Neurons and Astrocytes
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Krencik, Robert, Seo, Kyounghee, van Asperen, Jessy V, Basu, Nupur, Cvetkovic, Caroline, Barlas, Saba, Chen, Robert, Ludwig, Connor, Wang, Chao, Ward, Michael E, Gan, Li, Horner, Philip J, Rowitch, David H, and Ullian, Erik M
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Stem Cell Research ,Stem Cell Research - Embryonic - Human ,Stem Cell Research - Induced Pluripotent Stem Cell ,Bioengineering ,Neurosciences ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Neurological ,Astrocytes ,Cell Differentiation ,Cell Lineage ,Cells ,Cultured ,Coculture Techniques ,Humans ,Neural Stem Cells ,Neurons ,Pluripotent Stem Cells ,Synapses ,astrocytes ,coculture ,disease modeling ,human pluripotent stem cells ,neurons ,organoids ,synapses ,three-dimensional spheres ,Clinical Sciences ,Biochemistry and cell biology - Abstract
Human astrocytes network with neurons in dynamic ways that are still poorly defined. Our ability to model this relationship is hampered by the lack of relevant and convenient tools to recapitulate this complex interaction. To address this barrier, we have devised efficient coculture systems utilizing 3D organoid-like spheres, termed asteroids, containing pre-differentiated human pluripotent stem cell (hPSC)-derived astrocytes (hAstros) combined with neurons generated from hPSC-derived neural stem cells (hNeurons) or directly induced via Neurogenin 2 overexpression (iNeurons). Our systematic methods rapidly produce structurally complex hAstros and synapses in high-density coculture with iNeurons in precise numbers, allowing for improved studies of neural circuit function, disease modeling, and drug screening. We conclude that these bioengineered neural circuit model systems are reliable and scalable tools to accurately study aspects of human astrocyte-neuron functional properties while being easily accessible for cell-type-specific manipulations and observations.
- Published
- 2017
24. Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage
- Author
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Petersen, Mark A, Ryu, Jae Kyu, Chang, Kae-Jiun, Etxeberria, Ainhoa, Bardehle, Sophia, Mendiola, Andrew S, Kamau-Devers, Wanjiru, Fancy, Stephen PJ, Thor, Andrea, Bushong, Eric A, Baeza-Raja, Bernat, Syme, Catriona A, Wu, Michael D, Coronado, Pamela E Rios, Meyer-Franke, Anke, Yahn, Stephanie, Pous, Lauriane, Lee, Jae K, Schachtrup, Christian, Lassmann, Hans, Huang, Eric J, Han, May H, Absinta, Martina, Reich, Daniel S, Ellisman, Mark H, Rowitch, David H, Chan, Jonah R, and Akassoglou, Katerina
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Regenerative Medicine ,Stem Cell Research - Nonembryonic - Non-Human ,Neurodegenerative ,Multiple Sclerosis ,Stem Cell Research ,Brain Disorders ,Autoimmune Disease ,Stem Cell Research - Nonembryonic - Human ,Hematology ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Cardiovascular ,Neurological ,Activin Receptors ,Type I ,Animals ,Blood Vessels ,Bone Morphogenetic Proteins ,Fibrinogen ,Lysophosphatidylcholines ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Microarray Analysis ,Myelin Sheath ,Oligodendrocyte Precursor Cells ,Plasmids ,Remyelination ,Signal Transduction ,NG2 cells ,ancrod ,cell fate ,fibrin ,myelin ,neonatal brain injury ,neuroinflammation ,regeneration ,stem/progenitor cells ,vasculature ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.
- Published
- 2017
25. Diversity and Function of Glial Cell Types in Multiple Sclerosis
- Author
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Schirmer, Lucas, Schafer, Dorothy P., Bartels, Theresa, Rowitch, David H., and Calabresi, Peter A.
- Published
- 2021
- Full Text
- View/download PDF
26. Extensive migration of young neurons into the infant human frontal lobe
- Author
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Paredes, Mercedes F, James, David, Gil-Perotin, Sara, Kim, Hosung, Cotter, Jennifer A, Ng, Carissa, Sandoval, Kadellyn, Rowitch, David H, Xu, Duan, McQuillen, Patrick S, Garcia-Verdugo, Jose-Manuel, Huang, Eric J, and Alvarez-Buylla, Arturo
- Subjects
Biological Psychology ,Biomedical and Clinical Sciences ,Psychology ,Pediatric ,Neurosciences ,1.1 Normal biological development and functioning ,Underpinning research ,Neurological ,Cell Movement ,Doublecortin Domain Proteins ,Frontal Lobe ,Gyrus Cinguli ,Humans ,Infant ,Interneurons ,Lateral Ventricles ,Microtubule-Associated Proteins ,Neurogenesis ,Neuronal Plasticity ,Neurons ,Neuropeptides ,General Science & Technology - Abstract
The first few months after birth, when a child begins to interact with the environment, are critical to human brain development. The human frontal lobe is important for social behavior and executive function; it has increased in size and complexity relative to other species, but the processes that have contributed to this expansion are unknown. Our studies of postmortem infant human brains revealed a collection of neurons that migrate and integrate widely into the frontal lobe during infancy. Chains of young neurons move tangentially close to the walls of the lateral ventricles and along blood vessels. These cells then individually disperse long distances to reach cortical tissue, where they differentiate and contribute to inhibitory circuits. Late-arriving interneurons could contribute to developmental plasticity, and the disruption of their postnatal migration or differentiation may underlie neurodevelopmental disorders.
- Published
- 2016
27. The Role of the Neurointensive Care Nursery for Neonatal Encephalopathy
- Author
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Glass, Hannah C and Rowitch, David H
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Paediatrics ,Biomedical and Clinical Sciences ,Pediatric ,Neurosciences ,Physical Injury - Accidents and Adverse Effects ,Brain Disorders ,Prevention ,Perinatal Period - Conditions Originating in Perinatal Period ,Neurodegenerative ,Infant Mortality ,Reproductive health and childbirth ,Good Health and Well Being ,Cooperative Behavior ,Hospital Units ,Humans ,Hypoxia-Ischemia ,Brain ,Infant ,Newborn ,Intensive Care Units ,Neonatal ,Neonatologists ,Neurologists ,Neurology ,Neurocritical care ,Infant ,Critical care ,Therapeutic hypothermia ,Neonatal seizures ,Cerebral palsy ,Neonatal encephalopathy ,Hypoxic-ischemic encephalopathy ,Clinical Sciences ,Paediatrics and Reproductive Medicine ,Pediatrics ,Reproductive medicine - Abstract
Neonatal encephalopathy due to intrapartum events is estimated at 1 to 2 per 1000 live births in high-income countries. Outcomes have improved over the past decade due to implementation of therapeutic hypothermia, the only clinically available neuroprotective strategy for hypoxic-ischemic encephalopathy. Neonatal encephalopathy is the most common condition treated within a neonatal neurocritical care unit. Neonates with encephalopathy benefit from a neurocritical care approach due to prevention of secondary brain injury through attention to basic physiology, earlier recognition and treatment of neurologic complications, consistent management using guidelines and protocols, and use of optimized teams at dedicated referral centers.
- Published
- 2016
28. Dysregulation of astrocyte extracellular signaling in Costello syndrome
- Author
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Krencik, Robert, Hokanson, Kenton C, Narayan, Aditi R, Dvornik, Jill, Rooney, Gemma E, Rauen, Katherine A, Weiss, Lauren A, Rowitch, David H, and Ullian, Erik M
- Subjects
Medical Biotechnology ,Biomedical and Clinical Sciences ,Neurosciences ,Stem Cell Research - Induced Pluripotent Stem Cell ,Rare Diseases ,Stem Cell Research ,Brain Disorders ,Genetics ,Intellectual and Developmental Disabilities (IDD) ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Neurological ,Animals ,Astrocytes ,Cell Differentiation ,Cell Line ,Costello Syndrome ,Extracellular Matrix ,Gene Expression Regulation ,Genes ,ras ,Genotype ,Hippocampus ,Humans ,Induced Pluripotent Stem Cells ,Mass Spectrometry ,Mice ,Mice ,Transgenic ,Mutation ,Neuronal Plasticity ,Neurons ,Oligonucleotide Array Sequence Analysis ,Phenotype ,Proteoglycans ,Signal Transduction ,Snail Family Transcription Factors ,Transcription Factors ,ras Proteins ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - Abstract
Astrocytes produce an assortment of signals that promote neuronal maturation according to a precise developmental timeline. Is this orchestrated timing and signaling altered in human neurodevelopmental disorders? To address this question, the astroglial lineage was investigated in two model systems of a developmental disorder with intellectual disability caused by mutant Harvey rat sarcoma viral oncogene homolog (HRAS) termed Costello syndrome: mutant HRAS human induced pluripotent stem cells (iPSCs) and transgenic mice. Human iPSCs derived from patients with Costello syndrome differentiated to astroglia more rapidly in vitro than those derived from wild-type cell lines with normal HRAS, exhibited hyperplasia, and also generated an abundance of extracellular matrix remodeling factors and proteoglycans. Acute treatment with a farnesyl transferase inhibitor and knockdown of the transcription factor SNAI2 reduced expression of several proteoglycans in Costello syndrome iPSC-derived astrocytes. Similarly, mice in which mutant HRAS was expressed selectively in astrocytes exhibited experience-independent increased accumulation of perineuronal net proteoglycans in cortex, as well as increased parvalbumin expression in interneurons, when compared to wild-type mice. Our data indicate that astrocytes expressing mutant HRAS dysregulate cortical maturation during development as shown by abnormal extracellular matrix remodeling and implicate excessive astrocyte-to-neuron signaling as a possible drug target for treating mental impairment and enhancing neuroplasticity.
- Published
- 2015
29. Postnatal growth of the human pons: A morphometric and immunohistochemical analysis
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Tate, Matthew C, Lindquist, Robert A, Nguyen, Thuhien, Sanai, Nader, Barkovich, A James, Huang, Eric J, Rowitch, David H, and Alvarez‐Buylla, Arturo
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Biomedical and Clinical Sciences ,Clinical Sciences ,Neurosciences ,Pediatric ,1.1 Normal biological development and functioning ,Underpinning research ,Adolescent ,Analysis of Variance ,Basic Helix-Loop-Helix Transcription Factors ,Cell Proliferation ,Child ,Child ,Preschool ,Female ,Humans ,Infant ,Infant ,Newborn ,Ki-67 Antigen ,Magnetic Resonance Imaging ,Male ,Myelin Sheath ,Nerve Tissue Proteins ,Oligodendrocyte Transcription Factor 2 ,Pons ,brainstem ,pediatric ,development ,basis ,pontine glioma ,nif-0000-00217 ,SciRes_000114 ,AB_304558 ,AB_2109815 ,AB_442102 ,AB_396287 ,AB_92396 ,AB_91107 ,AB_291466 ,AB_2336877 ,AB_2336878 ,AB_261856 ,AB_2304493 ,Basis ,Brainstem ,Development ,Nif-0000-00217 ,Pontine glioma ,Zoology ,Medical Physiology ,Neurology & Neurosurgery - Abstract
Despite its critical importance to global brain function, the postnatal development of the human pons remains poorly understood. In the present study, we first performed magnetic resonance imaging (MRI)-based morphometric analyses of the postnatal human pons (0-18 years; n = 6-14/timepoint). Pons volume increased 6-fold from birth to 5 years, followed by continued slower growth throughout childhood. The observed growth was primarily due to expansion of the basis pontis. T2-based MRI analysis suggests that this growth is linked to increased myelination, and histological analysis of myelin basic protein in human postmortem specimens confirmed a dramatic increase in myelination during infancy. Analysis of cellular proliferation revealed many Ki67(+) cells during the first 7 months of life, particularly during the first month, where proliferation was increased in the basis relative to tegmentum. The majority of proliferative cells in the postnatal pons expressed the transcription factor Olig2, suggesting an oligodendrocyte lineage. The proportion of proliferating cells that were Olig2(+) was similar through the first 7 months of life and between basis and tegmentum. The number of Ki67(+) cells declined dramatically from birth to 7 months and further decreased by 3 years, with a small number of Ki67(+) cells observed throughout childhood. In addition, two populations of vimentin/nestin-expressing cells were identified: a dorsal group near the ventricular surface, which persists throughout childhood, and a parenchymal population that diminishes by 7 months and was not evident later in childhood. Together, our data reveal remarkable postnatal growth in the ventral pons, particularly during infancy when cells are most proliferative and myelination increases.
- Published
- 2015
30. Astrocyte development and heterogeneity.
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Bayraktar, Omer Ali, Fuentealba, Luis C, Alvarez-Buylla, Arturo, and Rowitch, David H
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Cerebral Ventricles ,Spinal Cord ,Neuroglia ,Astrocytes ,Animals ,Mammals ,Humans ,Models ,Neurological ,Adult ,Neural Stem Cells ,Brain Disorders ,Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research ,Neurosciences ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological - Abstract
Astrocytes have many roles within the brain parenchyma, and a subpopulation restricted to germinal niches functions as neural stem cells (NSCs) that produce various types of neuronal progeny in relation to spatiotemporal factors. A growing body of evidence supports the concept of morphological and molecular differences between astrocytes in different brain regions, which might relate to their derivation from regionally patterned radial glia. Indeed, the notion that astrocytes are molecularly and functionally heterogeneous could help explain how the central nervous system (CNS) retains embryonic positional information into adulthood. Here, we discuss recent evidence for regionally encoded functions of astrocytes in the developing and adult CNS to provide an integrated concept of the origin and possible function of astrocyte heterogeneity. We focus on the regionalization of NSCs in the ventricular-subventricular zone (V-SVZ) of the adult mammalian brain and emerging evidence for a segmental organization of astrocytes in the developing spinal cord and forebrain. We propose that astrocytes' diversity will provide fundamental clues to understand regional brain organization and function.
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- 2014
31. Niche stiffness underlies the ageing of central nervous system progenitor cells
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Segel, Michael, Neumann, Björn, Hill, Myfanwy F. E., Weber, Isabell P., Viscomi, Carlo, Zhao, Chao, Young, Adam, Agley, Chibeza C., Thompson, Amelia J., Gonzalez, Ginez A., Sharma, Amar, Holmqvist, Staffan, Rowitch, David H., Franze, Kristian, Franklin, Robin J. M., and Chalut, Kevin J.
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- 2019
- Full Text
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32. Challenges to curing primary brain tumours
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Aldape, Kenneth, Brindle, Kevin M., Chesler, Louis, Chopra, Rajesh, Gajjar, Amar, Gilbert, Mark R., Gottardo, Nicholas, Gutmann, David H., Hargrave, Darren, Holland, Eric C., Jones, David T. W., Joyce, Johanna A., Kearns, Pamela, Kieran, Mark W., Mellinghoff, Ingo K., Merchant, Melinda, Pfister, Stefan M., Pollard, Steven M., Ramaswamy, Vijay, Rich, Jeremy N., Robinson, Giles W., Rowitch, David H., Sampson, John H., Taylor, Michael D., Workman, Paul, and Gilbertson, Richard J.
- Published
- 2019
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33. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children
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French, Courtney E., Delon, Isabelle, Dolling, Helen, Sanchis-Juan, Alba, Shamardina, Olga, Mégy, Karyn, Abbs, Stephen, Austin, Topun, Bowdin, Sarah, Branco, Ricardo G., Firth, Helen, NIHR BioResource—Rare Disease, Next Generation Children Project, Rowitch, David H., and Raymond, F. Lucy
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- 2019
- Full Text
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34. Single-cell reconstruction of the early maternal–fetal interface in humans
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Vento-Tormo, Roser, Efremova, Mirjana, Botting, Rachel A., Turco, Margherita Y., Vento-Tormo, Miquel, Meyer, Kerstin B., Park, Jong-Eun, Stephenson, Emily, Polański, Krzysztof, Goncalves, Angela, Gardner, Lucy, Holmqvist, Staffan, Henriksson, Johan, Zou, Angela, Sharkey, Andrew M., Millar, Ben, Innes, Barbara, Wood, Laura, Wilbrey-Clark, Anna, Payne, Rebecca P., Ivarsson, Martin A., Lisgo, Steve, Filby, Andrew, Rowitch, David H., Bulmer, Judith N., Wright, Gavin J., Stubbington, Michael J. T., Haniffa, Muzlifah, Moffett, Ashley, and Teichmann, Sarah A.
- Published
- 2018
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35. The Neonatal Gyrencephalic Cortex Maintains Regionally Distinct Streams of Neuroblasts
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Kim, Jaeyeon, primary, Sandoval, Kadellyn, additional, Poddar, Aunoy, additional, Chu, Julia, additional, Horton, Emma, additional, Cui, Di, additional, Nakamura, Keira, additional, Bartels, Theresa, additional, Wood, Christian, additional, Rowitch, David H, additional, Kim, Hosung, additional, Sherwood, Chet C, additional, Kramer, Boris W, additional, Roberts, Angela C, additional, ROSS, PABLO J, additional, Xu, Duan, additional, Robertson, Nicola J, additional, Ji, Peng, additional, Maga, Elizabeth A, additional, and Paredes, Mercedes F, additional
- Published
- 2023
- Full Text
- View/download PDF
36. Supplementary Figure 1 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
- Published
- 2023
- Full Text
- View/download PDF
37. Supplementary Figure 9 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
- Published
- 2023
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- View/download PDF
38. Supplementary Table 1 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
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- 2023
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39. Supplementary Figure 2 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
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- 2023
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40. Supplementary Figure 7 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
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- 2023
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41. Supplementary Figure 6 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
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- 2023
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- View/download PDF
42. Supplementary Figure 3 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
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- 2023
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43. Supplementary Figure 8 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
- Published
- 2023
- Full Text
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44. Supplementary Table 2 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
- Published
- 2023
- Full Text
- View/download PDF
45. Supplementary Table 4 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
- Published
- 2023
- Full Text
- View/download PDF
46. Supplementary Figure 4 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
- Published
- 2023
- Full Text
- View/download PDF
47. Supplementary Figure 5 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
- Published
- 2023
- Full Text
- View/download PDF
48. Supplementary Table 3 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
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Nicolaides, Theodore P., primary, Li, Huifang, primary, Solomon, David A., primary, Hariono, Sujatmi, primary, Hashizume, Rintaro, primary, Barkovich, Krister, primary, Baker, Suzanne J., primary, Paugh, Barbara S., primary, Jones, Chris, primary, Forshew, Tim, primary, Hindley, Guy F., primary, Hodgson, J. Graeme, primary, Kim, Jung-Sik, primary, Rowitch, David H., primary, Weiss, William A., primary, Waldman, Todd A., primary, and James, C. David, primary
- Published
- 2023
- Full Text
- View/download PDF
49. Supplementary Table 1 from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas
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Schiffman, Joshua D., primary, Hodgson, J. Graeme, primary, VandenBerg, Scott R., primary, Flaherty, Patrick, primary, Polley, Mei-Yin C., primary, Yu, Mamie, primary, Fisher, Paul G., primary, Rowitch, David H., primary, Ford, James M., primary, Berger, Mitchel S., primary, Ji, Hanlee, primary, Gutmann, David H., primary, and James, C. David, primary
- Published
- 2023
- Full Text
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50. Data from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas
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Schiffman, Joshua D., primary, Hodgson, J. Graeme, primary, VandenBerg, Scott R., primary, Flaherty, Patrick, primary, Polley, Mei-Yin C., primary, Yu, Mamie, primary, Fisher, Paul G., primary, Rowitch, David H., primary, Ford, James M., primary, Berger, Mitchel S., primary, Ji, Hanlee, primary, Gutmann, David H., primary, and James, C. David, primary
- Published
- 2023
- Full Text
- View/download PDF
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