SoxE regulation of Neural Crest Development

描述（由申请人提供）：神经嵴是一种多能干细胞群，其在脊椎动物胚胎中长距离迁移，并产生大量必需细胞类型，包括外周神经系统的神经元和神经胶质、黑素细胞、肾上腺的嗜铬细胞和大部分颅面骨骼。神经嵴细胞经历上皮向间充质转化（EMT），并从背侧神经管迁移，并在远处的靶位点定居，在那里它们产生这些衍生物。指导神经嵴细胞发育和分化的分子机制仍然知之甚少，然而，这些过程的一些关键转录调控因子已被确定。SoxE家族转录因子（Sox 8、Sox 9和Sox 10）对神经嵴细胞发育的几个方面至关重要，包括颅面骨骼的形成。SoxE因子在整个神经嵴发育过程中粘附性地起作用，以促进神经嵴细胞的初始形成、其干细胞状态的维持以及神经嵴衍生物的子集的分化。SoxE因子可通过其调节的一种机制是通过相关Sox蛋白家族SoxD蛋白（Sox 5/6/13）的作用。SoxD家族转录因子Sox 5在早期神经嵴细胞和包括骨骼组织在内的神经嵴衍生物的子集中表达。Sox 5似乎部分通过以环境依赖的方式调节Sox E因子的活性来发挥作用; Sox 5可以抑制Sox 10依赖的黑素细胞启动子激活，但与Sox 9合作驱动软骨细胞靶基因的转录。我发现Sox 5在非洲爪蟾神经嵴发育的许多阶段都有表达，并且在这种重要的细胞类型中起着重要的作用。在这个建议中，我将建立在这些强有力的初步研究结果，以更好地了解Sox 5在神经嵴发育过程中调节SoxE功能的作用。)

DESCRIPTION (provided by applicant): The neural crest is a multipotent stem cell population that migrates long distances in vertebrate embryos and gives rise to a large number of essential cell types including neurons and glia of the peripheral nervous system, melanocytes, chromaffin cells of the adrenal gland, and most of the craniofacial skeleton. Neural crest cells undergo an epithelial to mesenchymal transition (EMT), and migrate from the dorsal neural tube and populate distant target sites where they give rise to these derivatives. The molecular mechanisms that direct the development and differentiation of neural crest cells remains poorly understood, however, a number of key transcriptional regulators of these processes have been identified. SoxE family transcription factors (Sox8, Sox9, and Sox10) are essential for several aspects of neural crest cell development, including the formation of the craniofacial skeleton. SoxE factors act reiteratively throughout neural crest development to promote the initial formation of neural crest cells, the maintenance of their stem cell state, and the differentiation of a subset of neural crest derivatives. One mechanism via which SoxE factors can be regulated is through the actions of a family of related Sox proteins, the SoxD proteins (Sox5/6/13). The SoxD family transcription factor Sox5 is expressed in early neural crest cells and in a subset of neural crest derivatives including skeletal tissue. Where it has been examined, Sox5 appears to function in part by modulating the activity of SoxE factors in a context dependant fashion; Sox5 can inhibit Sox10-dependent activation of melanocyte promoters but cooperates with Sox9 to drive transcription of chondrocyte target genes. I have found that Sox5 is expressed throughout many stages of neural crest development in Xenopus and that it plays essential roles in this important cell type. In this proposal I will build on these strong preliminary findings in order to better understand the role of Sox5 in regulating SoxE function during neural crest development. )