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 Tfap2?. 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 Tfap2?, is one of the most conserved during evolution. In Human, mutations of the Tfap2? 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 Tfap2? expression in the Cranial Neural Crest cells, and to identify Human ADAM protein that can perform the same function.
The goal of the project is to understand how ADAM13, at the surface of the Cranial Neural Crest cells, controls the activity of Arid3a, in the nucleus, to induce the expression of Tfap2?. Both Arid3a and Tfap2? have been shown to be critical for normal Development of mammalian embryos and in particular, in human TFAP2? mutation cause the Branchio-Oculo-Facial syndrome.
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