Control of neural crest development in Xenopus

非洲爪蟾神经嵴发育的控制

• 批准号: 6845394
• 负责人: Jean-Pierre Saint-Jeannet
• 金额: $ 27.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845394
• 关键词: Xenopus; biological signal transduction; cartilage development; cell population study; chondrocytes; collagen; congenital oral /facial /cranial defect; congenital skeletal disorder; developmental genetics; embryo /fetus tissue /cell culture; embryogenesis; functional /structural genomics; gene expression; gene induction /repression; gene mutation; green fluorescent proteins; mixed tissue /cell culture; mutant; neural crest; protein protein interaction; steroid hormone; transcription factor

DESCRIPTION (provided by applicant): Sox proteins fall into a large class of transcription factors related to SRY, the testis determining factor. Expression of these proteins in defined cell types during embryogenesis appears to govern cell fate decisions. One member of this family, mouse Sox9, has been shown to regulate cartilage formation by binding and activating the chondrocyte specific enhancer of type II collagen (Col2a1). Consistent with this role, Col2a1 and Sox9 are coexpressed in all chondrogenic precursors. Mutations in Sox9 result in Campomelic Dysplasia (CD), a lethal human disorder characterized by XY sex reversal and severe skeletal malformations. During embryogenesis, Sox 9 is also expressed in neural crest progenitors. CD patients also present defects in craniofacial skeletal elements of neural crest origin (palate and jaws) suggesting that Sox9 may play an important role in cranial neural crest formation. Preliminary studies indicate that Sox9 is required for neural crest formation during Xenopus laevis development. Sox9 is expressed at the gastrula stage in the neural crest-forming region. In this tissue, Sox9 colocalizes spatially and temporally with Slug, known to be the earliest gene activated in response to neural crest-inducing signals. Depletion of Sox9 in developing embryos, using a novel antisense approach, causes a loss of neural crest progenitors and an expansion of neural tissues. Later during embryogenesis, antisense-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements, mimicking aspect of the craniofacial defects observed in CD patients. Our hypothesis is that the transcription factor Sox9 is an essential component of the signaling cascade leading to neural crest formation. We propose: 1)- To characterize Sox9 activity within the neural crest by defining the timing of Sox9 requirement for neural crest formation. 2)- To determine whether Sox9 activity is required for specific neural crest lineages, by targeting Sox9 depletion in areas of the neural fold fated to form either cranial or trunk crest derivatives. 3)- To define the origin and the nature of the signals regulating Sox9 expression in the neural folds. The spectrum of abnormalities in CD patients indicates a fundamental role of Sox9 in sex determination and skeletal development but also important roles in other developmental processes. The work proposed here will address the function of Sox9 in the signaling cascade leading to neural crest formation.

描述（由申请人提供）：Sox蛋白属于一大类 与睾丸决定因子SRY相关的转录因子。表达 在胚胎发生过程中，这些蛋白质在确定的细胞类型中似乎支配着 细胞命运的决定这个家族的一个成员，小鼠Sox 9，已经被证明是 通过结合和激活软骨细胞特异性的 II型胶原增强剂（Col2a1）。与此作用一致，Col2a1和 Sox 9在所有软骨形成前体中共表达。Sox9突变导致 在弓形体发育不良（CD）中，一种以XY性别为特征的致命性人类疾病 逆转和严重的骨骼畸形。在胚胎发育过程中，Sox 9也是 在神经嵴祖细胞中表达。CD患者也存在缺陷， 神经嵴起源的颅面骨骼成分（腭和颌） 提示Sox 9可能在颅神经嵴中起重要作用 阵 初步研究表明，Sox 9是神经嵴形成所必需的 在非洲爪蟾的发育过程中。Sox 9在原肠期表达， 神经嵴形成区在该组织中，Sox 9在空间上共定位， 时间上与鼻涕虫，已知是最早的基因激活响应 神经嵴诱导信号在发育中的胚胎中耗尽Sox 9，使用 一种新的反义方法，导致神经嵴祖细胞的损失， 神经组织的扩张后来在胚胎发生过程中，反义处理 胚胎有一个特定的损失或减少神经嵴衍生的骨骼 元素，模仿CD患者中观察到的颅面缺陷的方面。 我们的假设是转录因子Sox 9是一个重要的组成部分， 导致神经嵴形成的信号级联。我们建议：1） 通过定义Sox9的时间来表征神经嵴内的Sox9活性， 神经嵴形成的Sox9要求。2)-为了确定Sox9 活性是特定神经嵴谱系所必需的，通过靶向Sox 9 注定要形成颅骨或躯干的神经褶皱区域的损耗 波峰导数3)-来确定信号的来源和性质 调节神经褶皱中Sox9的表达。 CD患者的异常谱表明， Sox 9在性别决定和骨骼发育中也发挥重要作用， 其他发展过程。这里提出的工作将解决的职能 Sox9在导致神经嵴形成的信号级联中的作用。