40 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. 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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10. 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
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11. Neuroinflammatory reactive astrocyte formation correlates with adverse outcomes in perinatal white matter injury.
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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
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- 2024
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12. 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
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- 2023
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13. 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
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- 2023
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14. 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
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- 2023
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15. 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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16. 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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17. 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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18. 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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19. 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
- Published
- 2023
- Full Text
- View/download PDF
20. Supplementary Figure 8 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
- Author
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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
21. Supplementary Table 2 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
- Author
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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
22. Supplementary Table 4 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
- Author
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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
23. Supplementary Figure 4 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
- Author
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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
24. Supplementary Figure 5 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
- Author
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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
25. Supplementary Table 3 from Targeted Therapy for BRAFV600E Malignant Astrocytoma
- Author
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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
26. Supplementary Table 1 from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas
- Author
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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
27. Data from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas
- Author
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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
28. Supplementary Figure 1 from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas
- Author
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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
29. Supplementary Table 2 from Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas
- Author
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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
30. jamaneurology_morton_2022_rv_220001_1646244188.29201.pdf
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Morton, Sarah U, Christodoulou, John, Costain, Gregory, Muntoni, Francesco, Wakeling, Emma, Wojcik, Monica, French, Courtney E., Szuto, Anna, Dowling, James J., D. Cohn, Ronald, Raymond, F. Lucy, T. Darras, Basil, A. Williams, David, Lunke, Sebastian, Stark, Zornitza, Rowitch, David H., and B. Agrawal, Pankaj
- Subjects
Infant and child health ,Neonatology - Abstract
IMPORTANCE Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease. OBSERVATIONS The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations. CONCLUSIONS AND RELEVANCE This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice.
- Published
- 2023
- Full Text
- View/download PDF
31. Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells
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Bulstrode, Harry, primary, Girdler, Gemma C., additional, Gracia, Tannia, additional, Aivazidis, Alexander, additional, Moutsopoulos, Ilias, additional, Young, Adam M.H., additional, Hancock, John, additional, He, Xiaoling, additional, Ridley, Katherine, additional, Xu, Zhaoyang, additional, Stockley, John H., additional, Finlay, John, additional, Hallou, Clement, additional, Fajardo, Teodoro, additional, Fountain, Daniel M., additional, van Dongen, Stijn, additional, Joannides, Alexis, additional, Morris, Robert, additional, Mair, Richard, additional, Watts, Colin, additional, Santarius, Thomas, additional, Price, Stephen J., additional, Hutchinson, Peter J.A., additional, Hodson, Emma J., additional, Pollard, Steven M., additional, Mohorianu, Irina, additional, Barker, Roger A., additional, Sweeney, Trevor R., additional, Bayraktar, Omer, additional, Gergely, Fanni, additional, and Rowitch, David H., additional
- Published
- 2022
- Full Text
- View/download PDF
32. Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood
- Author
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French, Courtney E., primary, Dolling, Helen, additional, Mégy, Karyn, additional, Sanchis-Juan, Alba, additional, Kumar, Ajay, additional, Delon, Isabelle, additional, Wakeling, Matthew, additional, Mallin, Lucy, additional, Agrawal, Shruti, additional, Austin, Topun, additional, Walston, Florence, additional, Park, Soo-Mi, additional, Parker, Alasdair, additional, Piyasena, Chinthika, additional, Bradbury, Kimberley, additional, Ellard, Sian, additional, Rowitch, David H., additional, and Raymond, F. Lucy, additional
- Published
- 2022
- Full Text
- View/download PDF
33. Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion
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Tanabe, Koji, Nobuta, Hiroko, Yang, Nan, Ang, Cheen Euong, Huie, Philip, Jordan, Sacha, Oldham, Michael C, Rowitch, David H, Wernig, Marius, Nobuta, Hiroko [0000-0003-1410-2086], Ang, Cheen Euong [0000-0002-9050-6122], Wernig, Marius [0000-0002-5309-515X], and Apollo - University of Cambridge Repository
- Subjects
Pelizaeus-Merzbacher Disease ,Induced Pluripotent Stem Cells ,Cell Differentiation ,Leukodystrophy ,Fibroblasts ,Oligodendrocyte ,Myelination ,Oligodendroglia ,Humans ,natural sciences ,Molecular Biology ,Direct lineage conversion ,Human ,Developmental Biology - Abstract
Funder: National Multiple Sclerosis Society; Id: http://dx.doi.org/10.13039/100000890, Funder: Association Européenne contre les Leucodystrophies; Id: http://dx.doi.org/10.13039/501100008731, Funder: New York Stem Cell Foundation; Id: http://dx.doi.org/10.13039/100003194, Funder: University of California, San Francisco; Id: http://dx.doi.org/10.13039/100008069, Funder: Sandler Foundation; Id: http://dx.doi.org/10.13039/100007100, Funder: Action Medical Research; Id: http://dx.doi.org/10.13039/501100000317, Funder: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Id: http://dx.doi.org/10.13039/100005984, Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272, Funder: Stanford University; Id: http://dx.doi.org/10.13039/100005492, Funder: Foundation Optic Atrophy 1, Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols ( Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts.
- Published
- 2022
34. Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood
- Author
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French, Courtney E, Dolling, Helen, Mégy, Karyn, Sanchis-Juan, Alba, Kumar, Ajay, Delon, Isabelle, Wakeling, Matthew, Mallin, Lucy, Agrawal, Shruti, Austin, Topun, Walston, Florence, Park, Soo-Mi, Parker, Alasdair, Piyasena, Chinthika, Bradbury, Kimberley, Next Generation Children’s Project Consortium, Ellard, Sian, Rowitch, David H, Raymond, F Lucy, Rowitch, David [0000-0002-0079-0060], and Apollo - University of Cambridge Repository
- Subjects
paediatrics ,rapid diagnostic whole genome ,genomics ,rare disease ,mendelian disorders - Abstract
To facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, SMN1/2 copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high a priori risk for rare pediatric disease presentations.
- Published
- 2022
- Full Text
- View/download PDF
35. Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review
- Author
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Morton, Sarah U., primary, Christodoulou, John, additional, Costain, Gregory, additional, Muntoni, Francesco, additional, Wakeling, Emma, additional, Wojcik, Monica H., additional, French, Courtney E., additional, Szuto, Anna, additional, Dowling, James J., additional, Cohn, Ronald D., additional, Raymond, F. Lucy, additional, Darras, Basil T., additional, Williams, David A., additional, Lunke, Sebastian, additional, Stark, Zornitza, additional, Rowitch, David H., additional, and Agrawal, Pankaj B., additional
- Published
- 2022
- Full Text
- View/download PDF
36. A retroviral origin of vertebrate myelin
- Author
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Ghosh, Tanay, primary, Almeida, Rafael G., additional, Zhao, Chao, additional, Mannioui, Abdelkrim, additional, Martin, Elodie, additional, Fleet, Alex, additional, Ginez Gonzalez, M, additional, Rowitch, David H, additional, Stott, Katherine, additional, Adams, Ian, additional, Zalc, Bernard, additional, Goldman, Nick, additional, Lyons, David A., additional, and Franklin, Robin JM, additional
- Published
- 2022
- Full Text
- View/download PDF
37. Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion.
- Author
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Koji Tanabe, Hiroko Nobuta, Nan Yang, Cheen Euong Ang, Huie Jr, Philip, Jordan, Sacha, Oldham, Michael C., Rowitch, David H., and Wernig, Marius
- Subjects
OLIGODENDROGLIA ,PLURIPOTENT stem cells ,CENTRAL nervous system ,FIBROBLASTS ,TRANSCRIPTION factors - Abstract
Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols (Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
38. Using Organoids to Model Sex Differences in the Human Brain
- Author
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Pavlinek, Adam, Adhya, Dwaipayan, Tsompanidis, Alex, Warrier, Varun, 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., Lancaster, Madeline, Mill, Jonathan, Srivastava, Deepak P., and Baron-Cohen, Simon
- Abstract
Sex differences are widespread during neurodevelopment and play a role in neuropsychiatric conditions such as autism, which is more prevalent in males than females. In humans, males have been shown to have larger brain volumes than females with development of the hippocampus and amygdala showing prominent sex differences. Mechanistically, sex steroids and sex chromosomes drive these differences in brain development, which seem to peak during prenatal and pubertal stages. Animal models have played a crucial role in understanding sex differences, but the study of human sex differences requires an experimental model that can recapitulate complex genetic traits. To fill this gap, human induced pluripotent stem cell–derived brain organoids are now being used to study how complex genetic traits influence prenatal brain development. For example, brain organoids from individuals with autism and individuals with X chromosome–linked Rett syndrome and fragile X syndrome have revealed prenatal differences in cell proliferation, a measure of brain volume differences, and excitatory-inhibitory imbalances. Brain organoids have also revealed increased neurogenesis of excitatory neurons due to androgens. However, despite growing interest in using brain organoids, several key challenges remain that affect its validity as a model system. In this review, we discuss how sex steroids and the sex chromosomes each contribute to sex differences in brain development. Then, we examine the role of X chromosome inactivation as a factor that drives sex differences. Finally, we discuss the combined challenges of modeling X chromosome inactivation and limitations of brain organoids that need to be taken into consideration when studying sex differences.
- Published
- 2024
- Full Text
- View/download PDF
39. Evidence for glutamine synthetase function in mouse spinal cord oligodendrocytes.
- Author
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Ben Haim, Lucile, Schirmer, Lucas, Zulji, Amel, Sabeur, Khalida, Tiret, Brice, Ribon, Matthieu, Chang, Sandra, Lamers, Wouter H., Boillée, Séverine, Chaumeil, Myriam M., and Rowitch, David H.
- Published
- 2021
- Full Text
- View/download PDF
40. Generation of Mammalian Astrocyte Functional Heterogeneity.
- Author
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Bartels T, Rowitch DH, and Bayraktar OA
- Abstract
Mammalian astrocytes have regional roles within the brain parenchyma. Indeed, the notion that astrocytes are molecularly heterogeneous could help explain how the central nervous system (CNS) retains embryonic positional information through development into specialized regions into adulthood. 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 and/or local neuron inductive cues. Here, we review evidence for regionally encoded functions of astrocytes to provide an integrated concept on lineage origins and heterogeneity to understand regional brain organization, as well as emerging technologies to identify and further investigate novel roles for astrocytes., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
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