PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Clustering Epilepsy

Neurobiology of Disease
Claire C HomanJozef Gecz

Abstract

PCDH19-Girls Clustering Epilepsy (PCDH19-GCE) is a childhood epileptic encephalopathy characterised by a spectrum of neurodevelopmental problems. PCDH19-GCE is caused by heterozygous loss-of-function mutations in the X-chromosome gene, Protocadherin 19 (PCDH19) encoding a cell-cell adhesion molecule. Intriguingly, hemizygous males are generally unaffected. As PCDH19 is subjected to random X-inactivation, heterozygous females are comprised of a mosaic of cells expressing either the normal or mutant allele, which is thought to drive pathology. Despite being the second most prevalent monogeneic cause of epilepsy, little is known about the role of PCDH19 in brain development. 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 ...Continue Reading

Citations

Nov 13, 2019·Brain and Behavior·Li YangBaomin Li
Sep 10, 2020·International Journal of Molecular Sciences·Akari TakaiTomohiro Chiyonobu
Jan 17, 2020·International Journal of Molecular Sciences·Bruno SterliniAnna Corradi
Oct 5, 2019·Materials·Natasha Antill-O'BrienCathal D O'Connell
Mar 5, 2019·Epilepsia·Danique R M VlaskampDanielle M Andrade
Feb 15, 2020·Pediatric Neurology·Debopam Samanta
Jul 3, 2021·Journal of Clinical Medicine·Rossella BorghiClaudia Compagnucci

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