The Role of GPR161 in the Etiology of Neural Tube Defects

摘要 神经管缺陷(NTD)是人类第二常见的结构性出生缺陷。它们是由 神经管闭合(NTC)失败。有多种与发育相关的信号 NTC在空间和时间上所涉及的通路。已知NTDS的原因是多方面的- 因素，包括遗传和环境因素。考虑到遗传因素对 神经管畸形的病因、特定基因变异的鉴定及其潜在的特征 在过去几年中，导致NTDS病因的分子和细胞机制进展缓慢 几十年。我们使用全基因组测序(WGS)从大样本中鉴定了GPR161的新的稀有变体 人类群体。GPR161是已知的Shh信号通路的负调控因子，Shh缺失的小鼠表达 NTD表型。GPR161vl和空小鼠模型表明，其他信号通路也参与其中。这个 Shh、Wnt和PCP信号通路参与了神经管构型、神经干细胞增殖、 在NTC期间，神经脊细胞通过细胞极化迁移。我们将使用以下特定假设来测试 体外和体内模型。(1)GPR161可调控Wnt和PCP信号通路，新发现的稀有基因 GPR161的变异体对这些信号通路产生不利影响，使NTC失控。(2)GPR161可以影响 细胞增殖和细胞极性分别通过Wnt和PCP信号，因此GPR161的NTD变体将 通过损害这些过程来增加NTD的易感性。(3)已鉴定的人类GPR161 NTD变异体， 单独或与其他PCP基因结合，将在敲入(KI)小鼠模型中产生NTD表型。 拟议的研究计划将提供新的分子、细胞、发育和遗传联系 在GPR161、Wnt和PCP信号通路之间，因为它们与参与的形态发生过程有关 全国过渡委员会正常。填补这个大的数据缺口可以引导我们找到新的治疗策略，既可以进行干预，也可以 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.