The Role of GPR161 in the Etiology of Neural Tube Defects

摘要 神经管缺陷（NTDs）是第二大常见的人类结构性出生缺陷。它们来自于 在神经形成期间神经管闭合失败（NTC）。有多种与发育相关的信号 在空间和时间上参与NTC过程的途径。NTD的原因已知是多方面的- 因素，包括遗传和环境因素。鉴于遗传因素对 NTD的病因学，特异性基因变异的鉴定及其潜在的 在过去的几年中，导致NTD病因学的分子和细胞机制进展缓慢， 几十年我们已经使用全基因组测序（WGS）从大规模细胞中鉴定了GPR 161的新的罕见变体。 人类队列GPR 161是Shh信号通路的已知负调节因子，Shh缺失小鼠表达GPR 161。 NTD表型。GPR 161 vl和无效小鼠模型表明其他信号传导途径的参与。的 Shh、Wnt和PCP信号通路参与神经管形成、神经干细胞增殖， NTC期间神经嵴细胞通过细胞极化迁移。我们将测试以下特定假设， 体外和体内模型。(1)GPR 161可以调节Wnt和PCP信号通路，新的稀有基因 GPR 161的变体对这些信号通路产生不利影响，从而使NTC失调。(2)GPR 161可以影响 细胞增殖和细胞极性，因此GPR 161的NTD变体将 通过损害这些过程来增加NTD敏感性。(3)鉴定的人GPR 161 NTD变体， 单独或与其它PCP基因组合将在敲入（KI）小鼠模型中产生NTD表型。 该研究计划将提供新的分子，细胞，发育和遗传联系 GPR 161，Wnt和PCP信号通路之间的联系，因为它们与参与 正常NTC。填补这一巨大的数据缺口可以引导我们找到新的治疗策略， 治疗

ABSTRACT Neural tube defects (NTDs) are the second most common human structural birth defect. They result from the failure of neural tube closure (NTC) during neurulation. There are multiple developmentally-related signaling pathways involved as NTC processes spatially and temporally. The causes of NTDs are known to be multi- factorial, including genetic and environmental factors. Given that the genetic factors contribute significantly to the etiology of NTDs, the identification of specific gene variants and the characterization of their underlying molecular and cellular mechanisms leading to the etiology of NTDs has progressed slowly over the last several decades. We have identified novel rare variants of GPR161 using whole genome sequencing (WGS) from large human cohorts. GPR161 is a known negative regulator of the Shh signaling pathway, and Shh null mice express NTD phenotypes. The GPR161vl and null mice models suggest the involvement of other signaling pathways. The Shh, Wnt and PCP signaling pathways are involved in the neural tube patterning, neural stem cell proliferation, and neural crest cell migration via cell polarization during NTC. We will test the following specific hypothesis with in vitro and in vivo models. (1) GPR161 can regulate Wnt and PCP signaling pathways, and the novel rare gene variants of GPR161 adversely impact these signaling pathways, which dysregulate NTC. (2) GPR161 can impact cell proliferation and cell polarity via Wnt and PCP signaling, respectively, thus the NTD variants of GPR161 will increase NTD susceptibility by compromising these processes. (3) The identified human GPR161 NTD variants, alone or in combination with other PCP genes, will produce NTD phenotypes in knock in (KI) mouse models. The proposed research program will provide the novel molecular, cellular, developmental and genetic links between GPR161, Wnt and PCP signaling pathways, as they relate to morphogenetic processes involved in normal NTC. Filling this large datagap can lead us to novel therapeutic strategies for both intervention and treatment.