Mechanisms of Neural Crest Induction and Craniofacial Disorders

摘要/摘要 多能神经嵴（NC）细胞的异常发育可导致一些最常见的 出生缺陷，称为神经损伤，包括颅面结构畸形，牙齿组织， 和周围神经系统。在人类中，RNA解旋酶DDX 3的突变导致智力低下， 具有多种潜在神经损伤的残疾;然而，DDX 3在NC发展中的功能是 未知在热带爪蟾中，一种用于研究NC发育的高度易处理的模型，DDX 3 下调AKT激酶活性和Wnt/β-连环蛋白信号传导，导致NC诱导减少。 本申请的目的是阐明DDX 3和下游信号分子在NC中的功能 诱导中心假设是DDX 3通过下游基因调控来诱导NC。 网络，其组件是正常的数控感应的关键。这项申请有三个具体目标。 第一个目标将确定DDX 3如何诱导NC，重点是了解DDX 3如何激活 Akt.第二个目的将研究AKT在DDX 3下游的NC诱导中的作用，以及AKT在DDX 3下游的NC诱导中的作用。 待检验的假设是AKT通过Wnt/β-连环蛋白信号传导发挥作用。第三个目标将考验 使用X的可行性热带假丝酵母作为研究疾病相关的人类DDX 3突变的模型 下游基因影响细胞信号传导和NC诱导。这项研究的结果应该 提供了新的见解的基本机制，数控诱导，以及病因学 由该网络中的多个基因突变引起的人类神经损伤。

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.