Pcdh19 Loss-of-Function Increases Neuronal Migration In Vitro but is Dispensable for Brain Development in Mice
Pcdh19 Loss-of-Function Increases Neuronal Migration In Vitro but is Dispensable for Brain Development in Mice
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DOI：
10.1038/srep26765
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发表时间：
2016-05-31
影响因子：
4.6
通讯作者：
Thomas, Paul Q.
中科院分区：
文献类型：
--
作者：
Pederick, Daniel T.;Homan, Claire C.;Thomas, Paul Q.
原钙粘蛋白19 （Pcdh19）是原钙粘蛋白超家族的一个x连锁基因，其成员主要在中枢神经系统中表达，并与细胞粘附、轴突引导和树突自我回避有关。人类杂合性功能缺失突变可导致儿童癫痫障碍PCDH19女孩聚类癫痫（PCDH19 GCE），这表明PCDH19是大脑发育所必需的。然而，了解PCDH19在体内的功能已被证明具有挑战性，并且尚未在哺乳动物模型中进行研究。在这里，我们验证了一个小鼠Pcdh19空等位基因，其中β - geo报告盒在内源性启动子的控制下表达。对β - geo报告基因活性的分析显示，PCDH19在胚胎、出生后和成人大脑中广泛表达，但表达受限。Pcdh19（+/ β - geo）和Pcdh19（Y/ β - geo）脑组织未发现明显形态学缺陷，Pcdh19空细胞位置正常。然而，体外迁移实验显示，Pcdh19缺失神经元的运动性显著升高，这可能与Pcdh19突变患者的发病机制有关。总体而言，我们对Pcdh19（+/ β - geo）、Pcdh19（β - geo / β - geo）和Pcdh19（Y/ β - geo）小鼠的初步表征表明，尽管Pcdh19在中枢神经系统中广泛表达，并在人类癫痫中发挥作用，但其在小鼠中的功能对大脑发育并不是必需的。
Protocadherin 19 (Pcdh19) is an X-linked gene belonging to the protocadherin superfamily, whose members are predominantly expressed in the central nervous system and have been implicated in cell-cell adhesion, axon guidance and dendrite self-avoidance. Heterozygous loss-of-function mutations in humans result in the childhood epilepsy disorder PCDH19 Girls Clustering Epilepsy (PCDH19 GCE) indicating that PCDH19 is required for brain development. However, understanding PCDH19 function in vivo has proven challenging and has not been studied in mammalian models. Here, we validate a murine Pcdh19 null allele in which a beta-Geo reporter cassette is expressed under the control of the endogenous promoter. Analysis of beta-Geo reporter activity revealed widespread but restricted expression of PCDH19 in embryonic, postnatal and adult brains. No gross morphological defects were identified in Pcdh19(+/beta-Geo) and Pcdh19(Y/beta-Geo) brains and the location of Pcdh19 null cells was normal. However, in vitro migration assays revealed that the motility of Pcdh19 null neurons was significantly elevated, potentially contributing to pathogenesis in patients with PCDH19 mutations. Overall our initial characterization of Pcdh19(+/beta-Geo), Pcdh19(beta-Geo/beta-Geo) and Pcdh19(Y/beta-Geo) mice reveals that despite widespread expression of Pcdh19 in the CNS, and its role in human epilepsy, its function in mice is not essential for brain development.