PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Clustering Epilepsy
PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Clustering Epilepsy
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DOI：
10.1016/j.nbd.2018.05.004
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发表时间：
2018-08-01
影响因子：
6.1
通讯作者：
Gecz, Jozef
中科院分区：
文献类型：
--
作者：
Homan, Claire C.;Pederson, Stephen;Gecz, Jozef
pcdh19 -女孩群集性癫痫（PCDH19-GCE）是一种以一系列神经发育问题为特征的儿童癫痫性脑病。PCDH19- gce是由编码细胞-细胞粘附分子的x染色体基因原钙粘蛋白19 （PCDH19）的杂合性功能缺失突变引起的。有趣的是，半合子雄性通常不受影响。由于PCDH19遭受随机x失活，杂合雌性由表达正常或突变等位基因的细胞马赛克组成，这被认为是驱动病理的因素。尽管PCDH19是第二大常见的癫痫单基因原因，但人们对PCDH19在大脑发育中的作用知之甚少。在这项研究中，我们发现PCDH19在人类神经干细胞和祖细胞（NSPCs）中高度表达，并在体外研究了其在小鼠和人类来源的这些细胞中的功能。缺乏Pcdh19的小鼠NSPC的转录组学分析揭示了参与神经元分化调控的基因的变化，我们随后发现Pcdh19的缺失导致NSPC神经发生增加。我们将携带致病性PCDH19突变的人类成纤维细胞重编程为人类诱导多能干细胞（hiPSC），并利用这些细胞的神经分化将我们的研究扩展到人类NSPCs。与小鼠一样，PCDH19功能的丧失导致神经发生增加，此外，我们发现这与人类NSPC极性的丧失有关。总的来说，我们的数据表明PCDH19在调节哺乳动物皮层神经发生中的保守作用，并可能影响PCDH19- gce的发病机制。我们认为，同一个体内源自PCDH19野生型和突变型NSPCs的神经元细胞产生的时间差异或“异时性”可能导致下游神经元网络形成的不同步和异常，这在一定程度上使个体易发生网络功能障碍和癫痫活动。
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 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.