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，在脊椎动物胚胎中长距离迁移，并产生大量必需的细胞类型，包括周围神经系统的神经元和胶质细胞、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细胞到间充质细胞的转变（EMT），并从背神经管迁移到遥远的目标部位，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，已经确定了这些过程的一些关键转录调节因子。SoxE家族转录因子（Sox8、Sox9和Sox10）在神经嵴细胞发育的几个方面都是必不可少的，包括颅面骨骼的形成。SoxE因子在整个神经嵴发育过程中反复发挥作用，促进神经嵴细胞的初始形成，维持其干细胞状态，以及神经嵴衍生物子集的分化。SoxE因子调控的一种机制是通过相关的Sox蛋白家族SoxD蛋白的作用（Sox5/6/13）。SoxD家族转录因子Sox5在早期神经嵴细胞和包括骨组织在内的神经嵴衍生物子集中表达。在研究中，Sox5似乎部分通过以上下文依赖的方式调节Sox5因子的活性来起作用；Sox5可以抑制sox10依赖性黑素细胞启动子的激活，但与Sox9合作驱动软骨细胞靶基因的转录。我发现Sox5在爪蟾神经嵴发育的许多阶段都有表达，它在这种重要的细胞类型中起着至关重要的作用。在本提案中，我将以这些强有力的初步发现为基础，以便更好地理解Sox5在神经嵴发育过程中调节SoxE功能中的作用。

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. )