Mechanism of Cranial Neural Crest Cell Migration

4123 项目概要： 567颅神经嵴细胞是天然的干细胞，出生在神经干细胞之间的边界。 （未来的大脑）和非神经外胚层（未来的皮肤），存在于每一个脊椎动物。一旦建立 这些细胞向胚胎的前部移动，形成所有的面部结构，包括骨骼， 1089个软骨、肌肉和神经节。当这个过程出错时（占所有出生缺陷的三分之一）， 非常严重的颅面缺陷此外，细胞在胚胎内移动的方法 并侵入其他组织器官的过程类似于癌症转移的过程。因此 了解这些细胞如何在胚胎中移动至关重要。我们研究了这些细胞在 非洲爪蟾的脊椎动物胚胎，一个建立良好的模型，允许详细的研究 1143在哺乳动物胚胎中不可能。具体来说，可以产生数千个胚胎 每次实验，它们都在一个培养皿中发育，这样就不需要牺牲母亲， 1156个发展阶段很容易观察。基因组是已知的， 与人类的对应物保持一致。这项计划的目标是了解一种蛋白质 蛋白酶ADAM 13可以修饰转录因子的功能， Arid3a产生更多的另一种转录因子Tfap2 α。ADAM 13是一种金属蛋白酶， 1290切割细胞表面的其他蛋白质，而转录因子与细胞核中的DNA结合， 表达或抑制基因。我们对这两种转录因子特别感兴趣， 2212 Arid3a已被证明控制哺乳动物胚胎中的第一个细胞决定，以产生 胚胎或胎盘。因此，了解它是如何监管的至关重要。第二 2234转录因子Tfap 2 α是进化过程中最保守的转录因子之一。在人类中， Tfap 2 α基因已被证明是引起鳃-眼-面综合征（BOF）的致病基因。这种综合征 2256新生儿表现为面部结构缺陷、发育迟缓、皮肤创伤、耳畸形 和耳聋。我们打算研究ADAM13如何控制Arid3a功能和Tfap 2 α表达， 颅神经嵴细胞，并鉴定可以执行相同功能的人ADAM蛋白 功能

4123 PROJECT SUMMARY: 567 The cranial neural crest cells are natural stem cells that are born at the border between the neural (future brain) and non-neural ectoderm (future skin) that exist in every vertebrate. Once established these cells, move toward the front of the embryo to make all of the facial structures, including bones, 1089 cartilages, muscle and ganglia. When this process goes wrong (one third of all birth defects) it creates very serious craniofacial defects. In addition, the method by which the cells move within the embryo and invade other tissues and organs is similar to the process of cancer metastasis. Thus 1121 understanding how these cells move in the embryo is critical. We study the migration of these cells in the vertebrate embryo of the frog Xenopus Laevis, a well established model that allows detailed study 1143 that are not possible in mammalian embryos. Specifically, thousands of embryos can be generated for each experiment, they develop in a dish so that the mother does not need to be sacrificed, and all 1156 stages of development are easy to observe. The genome is known and most genes are well conserved with their human counterpart. The goal of this proposal is to understand how, one protein 1178 at the surface of the cell, the protease ADAM13, can modify the function of a transcription factor Arid3a to produce more of another transcription factor Tfap2α. ADAM13 is a metalloprotease that 1290 cuts other proteins at the surface of cells, while transcription factors bind to DNA in the nucleus to either express or suppress genes. We are particularly interested in these two transcription factors as 2212 Arid3a has been shown to control the first cell decision in mammalian embryos to produce the embryo proper or the placenta. Thus understanding how it is regulated is critical. The second 2234 transcription factor Tfap2α, is one of the most conserved during evolution. In Human, mutations of the Tfap2α gene have been shown to cause Branchio-Oculo-Facial syndrome (BOF). This syndrome is 2256 manifested in newborn as defects in structures of the face, growth delay, skin wound, malformed ears and deafness. We propose to study how ADAM13 controls Arid3a function and Tfap2α expression in the Cranial Neural Crest cells, and to identify Human ADAM protein that can perform the same function.