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4. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Author

Hengel, Holger, Bosso-Lefèvre, Célia, Grady, George, Szenker-Ravi, Emmanuelle, Li, Hankun, Pierce, Sarah, Lebigot, Élise, Tan, Thong-Teck, Eio, Michelle Y, Narayanan, Gunaseelan, Utami, Kagistia Hana, Yau, Monica, Handal, Nader, Deigendesch, Werner, Keimer, Reinhard, Marzouqa, Hiyam M, Gunay-Aygun, Meral, Muriello, Michael J, Verhelst, Helene, Weckhuysen, Sarah, Mahida, Sonal, Naidu, Sakkubai, Thomas, Terrence G, Lim, Jiin Ying, Tan, Ee Shien, Haye, Damien, Willemsen, Michèl AAP, Oegema, Renske, Mitchell, Wendy G, Pierson, Tyler Mark, Andrews, Marisa V, Willing, Marcia C, Rodan, Lance H, Barakat, Tahsin Stefan, van Slegtenhorst, Marjon, Gavrilova, Ralitza H, Martinelli, Diego, Gilboa, Tal, Tamim, Abdullah M, Hashem, Mais O, AlSayed, Moeenaldeen D, Abdulrahim, Maha M, Al-Owain, Mohammed, Awaji, Ali, Mahmoud, Adel AH, Faqeih, Eissa A, Asmari, Ali Al, Algain, Sulwan M, Jad, Lamyaa A, Aldhalaan, Hesham M, Helbig, Ingo, Koolen, David A, Riess, Angelika, Kraegeloh-Mann, Ingeborg, Bauer, Peter, Gulsuner, Suleyman, Stamberger, Hannah, Ng, Alvin Yu Jin, Tang, Sha, Tohari, Sumanty, Keren, Boris, Schultz-Rogers, Laura E, Klee, Eric W, Barresi, Sabina, Tartaglia, Marco, Mor-Shaked, Hagar, Maddirevula, Sateesh, Begtrup, Amber, Telegrafi, Aida, Pfundt, Rolph, Schüle, Rebecca, Ciruna, Brian, Bonnard, Carine, Pouladi, Mahmoud A, Stewart, James C, Claridge-Chang, Adam, Lefeber, Dirk J, Alkuraya, Fowzan S, Mathuru, Ajay S, Venkatesh, Byrappa, Barycki, Joseph J, Simpson, Melanie A, Jamuar, Saumya S, Schöls, Ludger, and Reversade, Bruno

Subjects
Organoids, Animals, Zebrafish, Humans, Epilepsy, Syndrome, Oxidoreductases, Pedigree, Kinetics, Genes, Recessive, Alleles, Adolescent, Child, Child, Preschool, Infant, Female, Male, Protein Domains, Loss of Function Mutation, Preschool, Genes, Recessive
Abstract

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Published
2020

7. Katanin p80 Regulates Human Cortical Development by Limiting Centriole and Cilia Number

Author

Hu, Wen F, Pomp, Oz, Ben-Omran, Tawfeg, Kodani, Andrew, Henke, Katrin, Mochida, Ganeshwaran H, Yu, Timothy W, Woodworth, Mollie B, Bonnard, Carine, Raj, Grace Selva, Tan, Thong Teck, Hamamy, Hanan, Masri, Amira, Shboul, Mohammad, Saffar, Muna Al, Partlow, Jennifer N, Al-Dosari, Mohammed, Alazami, Anas, Alowain, Mohammed, Alkuraya, Fowzan S, Reiter, Jeremy F, Harris, Matthew P, Reversade, Bruno, and Walsh, Christopher A

Subjects
Congenital Structural Anomalies, Pediatric, Rare Diseases, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Adenosine Triphosphatases, Animals, Case-Control Studies, Cell Proliferation, Centrioles, Cerebral Cortex, Cilia, Embryo, Mammalian, Embryonic Development, Fibroblasts, Hedgehog Proteins, Humans, Katanin, Mice, Microcephaly, Mutation, Pedigree, RNA Splicing, White People, Zebrafish, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.

Published
2014

8. RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6

Author

Szenker-Ravi, Emmanuelle, Altunoglu, Umut, Leushacke, Marc, Bosso-Lefèvre, Célia, Khatoo, Muznah, Thi Tran, Hong, Naert, Thomas, Noelanders, Rivka, Hajamohideen, Amin, Beneteau, Claire, de Sousa, Sergio B., Karaman, Birsen, Latypova, Xenia, Başaran, Seher, Yücel, Esra Börklü, Tan, Thong Teck, Vlaminck, Lena, Nayak, Shalini S., Shukla, Anju, Girisha, Katta Mohan, Le Caignec, Cédric, Soshnikova, Natalia, Uyguner, Zehra Oya, Vleminckx, Kris, Barker, Nick, Kayserili, Hülya, and Reversade, Bruno

Published
2018
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10. Author Correction: RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6

Author

Szenker-Ravi, Emmanuelle, Altunoglu, Umut, Leushacke, Marc, Bosso-Lefèvre, Célia, Khatoo, Muznah, Thi Tran, Hong, Naert, Thomas, Noelanders, Rivka, Hajamohideen, Amin, Beneteau, Claire, de Sousa, Sergio B., Karaman, Birsen, Latypova, Xenia, Başaran, Seher, Yücel, Esra Börklü, Tan, Thong Teck, Vlaminck, Lena, Nayak, Shalini S., Shukla, Anju, Girisha, Katta Mohan, Le Caignec, Cédric, Soshnikova, Natalia, Uyguner, Zehra Oya, Vleminckx, Kris, Barker, Nick, Kayserili, Hülya, and Reversade, Bruno

Published
2018
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11. Correction: A Micropatterned Human-Specific Neuroepithelial Tissue for Modeling Gene and Drug-Induced Neurodevelopmental Defects (Advanced Science, (2021), 8, 5, (2001100), 10.1002/advs.202001100)

Author

Sahni, Geetika, Chang, Shu-Yung, Teo, Jeremy Choon Meng, Tan, Jerome Zu Yao, Fatien, Jean Jacques Clement, Bonnard, Carine, Utami, Kagistia Hana, Chan, Puck Wee, Tan, Thong Teck, Altunoglu, Umut, Kayserili, H. lya, Pouladi, Mahmoud, Reversade, Bruno, Toh, Yi-Chin, ACS - Heart failure & arrhythmias, and Amsterdam Reproduction & Development (AR&D)

Abstract

In the originally published article, the first name and family name of the third author were mixed-up. The corrected author byline is presented here.

Published
2021

13. A Micropatterned Human‐Specific Neuroepithelial Tissue for Modeling Gene and Drug‐Induced Neurodevelopmental Defects

Author

Sahni, Geetika, primary, Chang, Shu‐Yung, additional, Teo, Jeremy Choon Meng, additional, Tan, Jerome Zu Yao, additional, Fatien, Jean Jacques Clement, additional, Bonnard, Carine, additional, Utami, Kagistia Hana, additional, Chan, Puck Wee, additional, Tan, Thong Teck, additional, Altunoglu, Umut, additional, Kayserili, Hülya, additional, Pouladi, Mahmoud, additional, Reversade, Bruno, additional, and Toh, Yi‐Chin, additional

Published
2021
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14. A micropatterned human-specific neuroepithelial tissue for modeling gene and drug-induced neurodevelopmental defects

Author

Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945); Reversade, Bruno, Sahni, Geetika; Chang, Shu-Yung; Meng, Jeremy Teo Choon; Tan, Jerome Zu Yao; Fatien, Jean Jacques Clement; Bonnard, Carine; Utami, Kagistia Hana; Chan, Puck Wee; Tan, Thong Teck; Altunoglu, Umut; Pouladi, Mahmoud; Toh, Yi-Chin, School of Medicine, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945); Reversade, Bruno, Sahni, Geetika; Chang, Shu-Yung; Meng, Jeremy Teo Choon; Tan, Jerome Zu Yao; Fatien, Jean Jacques Clement; Bonnard, Carine; Utami, Kagistia Hana; Chan, Puck Wee; Tan, Thong Teck; Altunoglu, Umut; Pouladi, Mahmoud; Toh, Yi-Chin, and School of Medicine

Abstract

The generation of structurally standardized human pluripotent stem cell (hPSC)-derived neural embryonic tissues has the potential to model genetic and environmental mediators of early neurodevelopmental defects. Current neural patterning systems have so far focused on directing cell fate specification spatio-temporally but not morphogenetic processes. Here, the formation of a structurally reproducible and highly-organized neuroepithelium (NE) tissue is directed from hPSCs, which recapitulates morphogenetic cellular processes relevant to early neurulation. These include having a continuous, polarized epithelium and a distinct invagination-like folding, where primitive ectodermal cells undergo E-to-N-cadherin switching and apical constriction as they acquire a NE fate. This is accomplished by spatio-temporal patterning of the mesoendoderm, which guides the development and self-organization of the adjacent primitive ectoderm into the NE. It is uncovered that TGF beta signaling emanating from endodermal cells support tissue folding of the prospective NE. Evaluation of NE tissue structural dysmorphia, which is uniquely achievable in the model, enables the detection of apical constriction and cell adhesion dysfunctions in patient-derived hPSCs as well as differentiating between different classes of neural tube defect-inducing drugs., Singapore Ministry of Education; N.1 Institute for Health; NUS Research Scholarships

Published
2021

16. Neurodevelopmental Defects: A Micropatterned Human‐Specific Neuroepithelial Tissue for Modeling Gene and Drug‐Induced Neurodevelopmental Defects (Adv. Sci. 5/2021)

Author

Sahni, Geetika, primary, Chang, Shu‐Yung, additional, Meng, Jeremy Teo Choon, additional, Tan, Jerome Zu Yao, additional, Fatien, Jean Jacques Clement, additional, Bonnard, Carine, additional, Utami, Kagistia Hana, additional, Chan, Puck Wee, additional, Tan, Thong Teck, additional, Altunoglu, Umut, additional, Kayserili, Hülya, additional, Pouladi, Mahmoud, additional, Reversade, Bruno, additional, and Toh, Yi‐Chin, additional

Published
2021
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17. A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling

Author

Bonnard, Carine, primary, Navaratnam, Naveenan, additional, Ghosh, Kakaly, additional, Chan, Puck Wee, additional, Tan, Thong Teck, additional, Pomp, Oz, additional, Ng, Alvin Yu Jin, additional, Tohari, Sumanty, additional, Changede, Rishita, additional, Carling, David, additional, Venkatesh, Byrappa, additional, Altunoglu, Umut, additional, Kayserili, Hülya, additional, and Reversade, Bruno, additional

Published
2020
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18. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Author

Genetica Klinische Genetica, Brain, Child Health, Hengel, Holger, Bosso-Lefèvre, Célia, Grady, George, Szenker-Ravi, Emmanuelle, Li, Hankun, Pierce, Sarah, Lebigot, Élise, Tan, Thong-Teck, Eio, Michelle Y, Narayanan, Gunaseelan, Utami, Kagistia Hana, Yau, Monica, Handal, Nader, Deigendesch, Werner, Keimer, Reinhard, Marzouqa, Hiyam M, Gunay-Aygun, Meral, Muriello, Michael J, Verhelst, Helene, Weckhuysen, Sarah, Mahida, Sonal, Naidu, Sakkubai, Thomas, Terrence G, Lim, Jiin Ying, Tan, Ee Shien, Haye, Damien, Willemsen, Michèl A A P, Oegema, Renske, Mitchell, Wendy G, Pierson, Tyler Mark, Andrews, Marisa V, Willing, Marcia C, Rodan, Lance H, Barakat, Tahsin Stefan, van Slegtenhorst, Marjon, Gavrilova, Ralitza H, Martinelli, Diego, Gilboa, Tal, Tamim, Abdullah M, Hashem, Mais O, AlSayed, Moeenaldeen D, Abdulrahim, Maha M, Al-Owain, Mohammed, Awaji, Ali, Mahmoud, Adel A H, Faqeih, Eissa A, Asmari, Ali Al, Algain, Sulwan M, Jad, Lamyaa A, Aldhalaan, Hesham M, Helbig, Ingo, Koolen, David A, Riess, Angelika, Kraegeloh-Mann, Ingeborg, Bauer, Peter, Gulsuner, Suleyman, Stamberger, Hannah, Ng, Alvin Yu Jin, Tang, Sha, Tohari, Sumanty, Keren, Boris, Schultz-Rogers, Laura E, Klee, Eric W, Barresi, Sabina, Tartaglia, Marco, Mor-Shaked, Hagar, Maddirevula, Sateesh, Begtrup, Amber, Telegrafi, Aida, Pfundt, Rolph, Schüle, Rebecca, Ciruna, Brian, Bonnard, Carine, Pouladi, Mahmoud A, Stewart, James C, Claridge-Chang, Adam, Lefeber, Dirk J, Alkuraya, Fowzan S, Mathuru, Ajay S, Venkatesh, Byrappa, Barycki, Joseph J, Simpson, Melanie A, Jamuar, Saumya S, Schöls, Ludger, Reversade, Bruno, Genetica Klinische Genetica, Brain, Child Health, Hengel, Holger, Bosso-Lefèvre, Célia, Grady, George, Szenker-Ravi, Emmanuelle, Li, Hankun, Pierce, Sarah, Lebigot, Élise, Tan, Thong-Teck, Eio, Michelle Y, Narayanan, Gunaseelan, Utami, Kagistia Hana, Yau, Monica, Handal, Nader, Deigendesch, Werner, Keimer, Reinhard, Marzouqa, Hiyam M, Gunay-Aygun, Meral, Muriello, Michael J, Verhelst, Helene, Weckhuysen, Sarah, Mahida, Sonal, Naidu, Sakkubai, Thomas, Terrence G, Lim, Jiin Ying, Tan, Ee Shien, Haye, Damien, Willemsen, Michèl A A P, Oegema, Renske, Mitchell, Wendy G, Pierson, Tyler Mark, Andrews, Marisa V, Willing, Marcia C, Rodan, Lance H, Barakat, Tahsin Stefan, van Slegtenhorst, Marjon, Gavrilova, Ralitza H, Martinelli, Diego, Gilboa, Tal, Tamim, Abdullah M, Hashem, Mais O, AlSayed, Moeenaldeen D, Abdulrahim, Maha M, Al-Owain, Mohammed, Awaji, Ali, Mahmoud, Adel A H, Faqeih, Eissa A, Asmari, Ali Al, Algain, Sulwan M, Jad, Lamyaa A, Aldhalaan, Hesham M, Helbig, Ingo, Koolen, David A, Riess, Angelika, Kraegeloh-Mann, Ingeborg, Bauer, Peter, Gulsuner, Suleyman, Stamberger, Hannah, Ng, Alvin Yu Jin, Tang, Sha, Tohari, Sumanty, Keren, Boris, Schultz-Rogers, Laura E, Klee, Eric W, Barresi, Sabina, Tartaglia, Marco, Mor-Shaked, Hagar, Maddirevula, Sateesh, Begtrup, Amber, Telegrafi, Aida, Pfundt, Rolph, Schüle, Rebecca, Ciruna, Brian, Bonnard, Carine, Pouladi, Mahmoud A, Stewart, James C, Claridge-Chang, Adam, Lefeber, Dirk J, Alkuraya, Fowzan S, Mathuru, Ajay S, Venkatesh, Byrappa, Barycki, Joseph J, Simpson, Melanie A, Jamuar, Saumya S, Schöls, Ludger, and Reversade, Bruno

Published
2020

19. Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita

Author

Xue, Shifeng, Maluenda, Jérôme, Marguet, Florent, Shboul, Mohammad, Quevarec, Loïc, Bonnard, Carine, Ng, Alvin Yu Jin, Tohari, Sumanty, Tan, Thong Teck, Kong, Mung Kei, Monaghan, Kristin G., Cho, Megan T., Siskind, Carly E., Sampson, Jacinda B., Rocha, Carolina Tesi, Alkazaleh, Fawaz, Gonzales, Marie, Rigonnot, Luc, Whalen, Sandra, Gut, Marta, Gut, Ivo, Bucourt, Martine, Venkatesh, Byrappa, Laquerrière, Annie, Reversade, Bruno, and Melki, Judith

Published
2017
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20. Attachment and growth of human embryonic stem cells on microcarriers

Author

Blaine Wesley Phillips, William Lathrop Rust, Tan Suat Lay, Rachel Horne, Jeremy M. Crook, and Tan Thong Teck

Subjects
Growth kinetics, Cell, Cell Culture Techniques, Bioengineering, Biology, Applied Microbiology and Biotechnology, Suspension culture, Adherent Culture, Cell Adhesion, medicine, Humans, Cells, Cultured, Embryonic Stem Cells, Cell Proliferation, Tissue Engineering, business.industry, Microcarrier, Embryo, Equipment Design, General Medicine, Embryonic stem cell, Biotechnology, Cell biology, Equipment Failure Analysis, medicine.anatomical_structure, embryonic structures, Stem cell, business
Abstract

The use of human embryonic stem cells (hESCs) for cell-based therapies will require large quantities of genetically stable pluripotent cells and their differentiated progeny. Traditional hESC propagation entails adherent culture and is sensitive to enzymatic dissociation. These constraints hamper modifying method from 2-dimensional flat-bed culture, which is expensive and impractical for bulk cell production. Large-scale culture for clinical use will require innovations such as suspension culture for bioprocessing. Here we describe the attachment and growth kinetics of both murine embryonic stem cells (mESCs) and hESCs on trimethyl ammonium-coated polystyrene microcarriers for feeder-free, 3-dimensional suspension culture. mESCs adhered and expanded according to standard growth kinetics. For hESC studies, we tested aggregate (collagenase-dissociated) and single-cell (TrypLE™-dissociated) culture. Cells attached rapidly to beads followed by proliferation. Single-cell cultures expanded 3-fold over approximately 5 days, slightly exceeding that of hESC aggregates. Importantly, single-cell cultures were maintained through 6 passages with a 14-fold increase in cell number while still expressing the undifferentiated markers Oct-4 and Tra 1-81. Finally, hESCs retained their capacity to differentiate towards pancreatic, neuronal, and cardiomyocyte lineages. Our studies provide proof-of-principle of suspension-based expansion of hESCs on microcarriers, as a novel, economical and practical feeder-free means of bulk hESC production.

Published
2008
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21. A deleterious recessive mutation in NUAK2 causes absence of brain in humans

Author

Ghosh, Kakaly, primary, Navaratnam, Naveenan, additional, Chan, Puck Wee, additional, Tan, Thong Teck, additional, Ng, Alvin Yu Jin, additional, Tohari, Sumanty, additional, Pomp, Oz, additional, Venkatesh, Byrappa, additional, Altunoglu, Umut, additional, Kayserili, Hülya, additional, Bonnard, Carine, additional, and Reversade, Bruno, additional

Published
2017
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22. Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics

Author

Jin, Mingyue, Pomp, Oz, Shinoda, Tomoyasu, Toba, Shiori, Torisawa, Takayuki, Furuta, Ken’ya, Oiwa, Kazuhiro, Yasunaga, Takuo, Kitagawa, Daiju, Matsumura, Shigeru, Miyata, Takaki, Tan, Thong Teck, Reversade, Bruno, Hirotsune, Shinji, Jin, Mingyue, Pomp, Oz, Shinoda, Tomoyasu, Toba, Shiori, Torisawa, Takayuki, Furuta, Ken’ya, Oiwa, Kazuhiro, Yasunaga, Takuo, Kitagawa, Daiju, Matsumura, Shigeru, Miyata, Takaki, Tan, Thong Teck, Reversade, Bruno, and Hirotsune, Shinji

Abstract

Human mutations in KATNB1 (p80) cause severe congenital cortical malformations, which encompass the clinical features of both microcephaly and lissencephaly. Although p80 plays critical roles during brain development, the underlying mechanisms remain predominately unknown. Here, we demonstrate that p80 regulates microtubule (MT) remodeling in combination with NuMA (nuclear mitotic apparatus protein) and cytoplasmic dynein. We show that p80 shuttles between the nucleus and spindle pole in synchrony with the cell cycle. Interestingly, this striking feature is shared with NuMA. Importantly, p80 is essential for aster formation and maintenance in vitro. siRNA-mediated depletion of p80 and/or NuMA induced abnormal mitotic phenotypes in cultured mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in the mouse embryonic brain. Importantly, these results were confirmed in p80-mutant harboring patient-derived induced pluripotent stem cells and brain organoids. Taken together, our findings provide valuable insights into the pathogenesis of severe microlissencephaly, in which p80 and NuMA delineate a common pathway for neurogenesis and neuronal migration via MT organization at the centrosome/spindle pole.

Published
2017

23. Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics

Author

Jin, Mingyue, primary, Pomp, Oz, additional, Shinoda, Tomoyasu, additional, Toba, Shiori, additional, Torisawa, Takayuki, additional, Furuta, Ken’ya, additional, Oiwa, Kazuhiro, additional, Yasunaga, Takuo, additional, Kitagawa, Daiju, additional, Matsumura, Shigeru, additional, Miyata, Takaki, additional, Tan, Thong Teck, additional, Reversade, Bruno, additional, and Hirotsune, Shinji, additional

Published
2017
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25. A Micropatterned Human-Specific Neuroepithelial Tissue for Modeling Gene and Drug-Induced Neurodevelopmental Defects

Author

Bruno Reversade, Jean Jacques Clement Fatien, Jerome Zu Yao Tan, Mahmoud A. Pouladi, Geetika Sahni, Jeremy Teo Choon Meng, Yi-Chin Toh, Hülya Kayserili, Shu Yung Chang, Puck Wee Chan, Thong Teck Tan, Umut Altunoglu, Carine Bonnard, Kagistia Hana Utami, ACS - Heart failure & arrhythmias, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Reversade, Bruno, Sahni, Geetika, Chang, Shu-Yung, Meng, Jeremy Teo Choon, Tan, Jerome Zu Yao, Fatien, Jean Jacques Clement, Bonnard, Carine, Utami, Kagistia Hana, Chan, Puck Wee, Tan, Thong Teck, Altunoglu, Umut, Pouladi, Mahmoud, Toh, Yi-Chin, and School of Medicine

Subjects
Drug, General Chemical Engineering, media_common.quotation_subject, Science, Neuroepithelial Tissue, General Physics and Astronomy, Medicine (miscellaneous), morphogenesis, Ectoderm, 02 engineering and technology, Cell fate determination, Biology, 010402 general chemistry, Chemistry, Nanoscience and nanotechnology, Materials science, 01 natural sciences, Biochemistry, Genetics and Molecular Biology (miscellaneous), Corrections, medicine, General Materials Science, human pluripotent stem cells, Human specific, lcsh:Science, Gene, media_common, neurodevelopmental defects, Full Paper, Neural tube, General Engineering, Correction, Apical constriction, Full Papers, neuroepithelium, 021001 nanoscience & nanotechnology, Embryonic stem cell, micropatterning, 0104 chemical sciences, Cell biology, Neuroepithelial cell, medicine.anatomical_structure, Neurulation, Human pluripotent stem cells, Micropatterning, Morphogenesis, Neurodevelopmental defects, Neuroepithelium, lcsh:Q, 0210 nano-technology, Neuroscience
Abstract

The generation of structurally standardized human pluripotent stem cell (hPSC)‐derived neural embryonic tissues has the potential to model genetic and environmental mediators of early neurodevelopmental defects. Current neural patterning systems have so far focused on directing cell fate specification spatio‐temporally but not morphogenetic processes. Here, the formation of a structurally reproducible and highly‐organized neuroepithelium (NE) tissue is directed from hPSCs, which recapitulates morphogenetic cellular processes relevant to early neurulation. These include having a continuous, polarized epithelium and a distinct invagination‐like folding, where primitive ectodermal cells undergo E‐to‐N‐cadherin switching and apical constriction as they acquire a NE fate. This is accomplished by spatio‐temporal patterning of the mesoendoderm, which guides the development and self‐organization of the adjacent primitive ectoderm into the NE. It is uncovered that TGFβ signaling emanating from endodermal cells support tissue folding of the prospective NE. Evaluation of NE tissue structural dysmorphia, which is uniquely achievable in the model, enables the detection of apical constriction and cell adhesion dysfunctions in patient‐derived hPSCs as well as differentiating between different classes of neural tube defect‐inducing drugs., This paper reports the generation of a reproducible and highly organized neuroepithelial (NE) tissue by combining human pluripotent stem cell (hPSC) micropatterning and a temporally sequenced induction protocol to specify NE cells in spatial juxtaposition to mesoendoderm cells. By evaluating NE tissue structural dysmorphia in the micropatterned NE model, we can successfully model gene‐ and drug‐induced neurodevelopmental defects.

Published
2021

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