| Autor: |
Scott Bell, Gilles Maussion, Malvin Jefri, Huashan Peng, Jean-Francois Theroux, Heika Silveira, Vincent Soubannier, Hanrong Wu, Peng Hu, Ekaterina Galat, S. Gabriela Torres-Platas, Camille Boudreau-Pinsonneault, Liam A. O'Leary, Vasiliy Galat, Gustavo Turecki, Thomas M. Durcan, Edward A. Fon, Naguib Mechawar, Carl Ernst |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Stem Cell Reports, Vol 11, Iss 1, Pp 183-196 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2213-6711 |
| DOI: |
10.1016/j.stemcr.2018.05.018 |
| Popis: |
Summary: Heterozygous loss-of-function mutations in GRIN2B, a subunit of the NMDA receptor, cause intellectual disability and language impairment. We developed clonal models of GRIN2B deletion and loss-of-function mutations in a region coding for the glutamate binding domain in human cells and generated neurons from a patient harboring a missense mutation in the same domain. Transcriptome analysis revealed extensive increases in genes associated with cell proliferation and decreases in genes associated with neuron differentiation, a result supported by extensive protein analyses. Using electrophysiology and calcium imaging, we demonstrate that NMDA receptors are present on neural progenitor cells and that human mutations in GRIN2B can impair calcium influx and membrane depolarization even in a presumed undifferentiated cell state, highlighting an important role for non-synaptic NMDA receptors. It may be this function, in part, which underlies the neurological disease observed in patients with GRIN2B mutations. : Mutations in GRIN2B cause intellectual disability and language impairments. In this study, Bell and colleagues engineer mutations in GRIN2B and repair a patient missense mutation to show an important role for GRIN2B and non-synaptic NMDA receptors in differentiating neural stem cells. Keywords: GRIN2B, NMDAR2B, NMDA, glutamate, iPSCs, CRISPR, CRISPR-Cas9, neurodevelopment, NPCs, neural stem cell |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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