PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Clustering Epilepsy.
In this study we show that PCDH19 is highly expressed in human neural stem and progenitor cells (NSPCs) and investigate its function in vitro in these cells of both mouse and human origin. Transcriptomic analysis of mouse NSPCs lacking Pcdh19 revealed changes to genes involved in regulation of neuronal differentiation, and we subsequently show that loss of Pcdh19 causes increased NSPC neurogenesis. We reprogramed human fibroblast cells harbouring a pathogenic PCDH19 mutation into human induced pluripotent stem cells (hiPSC) and employed neural differentiation of these to extend our studies into human NSPCs. As in mouse, loss of PCDH19 function caused increased neurogenesis, and furthermore, we show this is associated with a loss of human NSPC polarity. Overall our data suggests a conserved role for PCDH19 in regulating mammalian cortical neurogenesis and has implications for the pathogenesis of PCDH19-GCE. We propose that the difference in timing or "heterochrony" of neuronal cell production originating from PCDH19 wildtype and mutant NSPCs within the same individual may lead to downstream asynchronies and abnormalities in neuronal network formation, which in-part predispose the individual to network dysfunction and epileptic activity.
PMID: 29763708 [PubMed - as supplied by publisher]
Source: Neurobiology of Disease - Category: Neurology Authors: Homan CC, Pederson S, To TH, Tan C, Piltz S, Corbett M, Wolvetang E, Thomas P, Jolly LA, Gecz J Tags: Neurobiol Dis Source Type: research
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