Mechanism of Cranial Neural Crest Cell Migration

4123 项目总结： 567颅神经脊细胞是天然的干细胞，出生在神经细胞的交界处。 (未来的大脑)和非神经性外胚层(未来的皮肤)，存在于每一种脊椎动物中。一旦建立起来 这些细胞向胚胎的前部移动，形成包括骨骼在内的所有面部结构， 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)，它就会产生 非常严重的头面部缺陷。此外，细胞在胚胎内移动的方法 而侵袭其他组织器官的过程类似于癌症的转移过程。因此， 了解这些细胞如何在胚胎中移动是至关重要的。我们研究了这些细胞在体内的迁移 非洲爪蛙的脊椎动物胚胎，这是一个可以进行详细研究的成熟模型 这在哺乳动物胚胎中是不可能的。具体地说，可以产生数千个胚胎 对于每一次实验，它们都在一个盘子里发育，这样母亲就不需要被牺牲了，所有的 1156个发展阶段很容易观察。基因组是已知的，大多数基因都很好 与人类的同类保持一致。这项提议的目标是了解一种蛋白质是如何 在细胞表面，蛋白酶ADAM13可以改变转录因子的功能 Arid3a产生更多的另一种转录因子Tfap2α。ADAM13是一种金属蛋白水解酶 1290在细胞表面切割其他蛋白质，而转录因子与细胞核中的DNA结合以 表达或抑制基因。我们对这两个转录因子特别感兴趣，因为 2212 Arid3a已被证明控制着哺乳动物胚胎中产生 胚胎本身或胎盘。因此，理解它是如何受到监管的至关重要。第二 转录因子Tfap2α是进化过程中最保守的转录因子之一。在人类中，基因突变 Tfap2α基因已被证明是引起Branchio-Oculo-Face综合征的原因。这种综合症是 2256表现为新生儿面部结构缺陷、生长迟缓、皮肤损伤、耳朵畸形 还有耳聋。我们建议研究ADAM13是如何控制Arid3a功能和Tfap2α表达的。 脑神经脊细胞，并鉴定具有同样功能的人类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.