Mechanisms of Neural Crest Induction and Craniofacial Disorders

摘要/摘要 多能神经脊(NC)细胞的异常发育可导致一些最常见的 出生缺陷称为神经病变，包括头面部结构、牙齿组织、 以及外周神经系统。在人类中，RNA解旋酶DDX3的突变导致智力 有多种潜在神经病变的残疾；然而，DDX3在NC发育中的功能是 未知。在热带非洲爪哇，一种用于研究NC发育、DDX3耗竭的高度可处理的模型 下调AKT激酶活性和Wnt/β-catenin信号，导致NC诱导减少。 本申请的目的是阐明DDX3和下游信号分子在NC中如何发挥作用 归纳法。中心假说是DDX3通过下游基因调控诱导NC 网络，其组件对于正常的NC感应至关重要。这个应用程序有三个具体目标。 第一个目标将确定DDX3如何诱导NC，重点是了解DDX3是如何激活的 AKT。第二个目的是研究AKT在DDX3下游NC诱导中的作用，以及 有待检验的假设是，AKT通过Wnt/β-catenin信号发挥作用。第三个目标将考验 以热带疟原虫为模型研究人类DDX3基因突变与疾病相关的可行性 下游基因影响细胞信号转导和NC诱导。这项拟议研究的结果应该是 提供关于NC诱导的基本机制的新见解，以及 由这个网络中的多个基因突变引起的人类神经病变。

Summary/Abstract Aberrant development of the multipotent neural crest (NC) cells can result in some of the most common birth defects called neurocristopathies, including malformations of craniofacial structures, dental tissues, and the peripheral nervous system. In humans, mutations in the RNA helicase DDX3 cause intellectual disability with multiple potential neurocristopathies; however, the function of DDX3 in NC development is unknown. In Xenopus tropicalis, a highly tractable model for studying NC development, depletion of DDX3 downregulates the AKT kinase activity and Wnt/beta-catenin signaling, leading to reduced NC induction. The goal of this application is to elucidate how DDX3 and downstream signaling molecules function in NC induction. The central hypothesis is that DDX3 induces the NC through a downstream gene regulatory network, whose components are critical for normal NC induction. This application has three specific aims. The first aim will determine how DDX3 induces the NC, with a focus on understanding how DDX3 activates AKT. The second aim will investigate the roles of AKT in NC induction downstream of DDX3, and the hypothesis to be tested is that AKT functions through Wnt/beta-catenin signaling. The third aim will test the feasibility of using X. tropicalis as a model to study how diseases-associated human mutations in DDX3 and downstream genes affect cell signaling and NC induction. Outcomes of this proposed research should provide new insight into the fundamental mechanisms governing NC induction, as well as the etiology of human neurocristopathies caused by mutations in multiple genes in this network.