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蛋白属于一类 转录因子与SRY有关，即睾丸决定因子。表达 在胚胎发生过程中，这些蛋白质中的这些蛋白质似乎控制了 细胞命运决定。这个家庭的一个成员，鼠标Sox9，已显示为 通过结合和激活软骨细胞特异性来调节软骨形成 II型胶原蛋白的增强子（COL2A1）。与此角色一致，Col2a1和 Sox9在所有软骨的前体中共表达。 Sox9结果中的突变 在campomelic发育不良（CD）中，一种以XY性别为特征的致命人类疾病 逆转和严重的骨骼畸形。在胚胎发生过程中，Sox 9也是 在神经rest祖细胞中表达。 CD患者还出现缺陷 神经克雷斯特起源的颅面骨骼元素（pa and jaws） 暗示Sox9可能在颅神经rest中起重要作用 形成。 初步研究表明，神经rest形成需要Sox9 在Xenopus laevis开发期间。 Sox9在胃阶段表示 神经rest形区域。在该组织中，Sox9在空间和 暂时使用sl，已知是最早激活的基因 神经rest诱导的信号。 Sox9在开发胚胎中的耗竭 新颖的反义方法会导致神经rest祖细胞的丧失和 神经组织的扩展。后来在胚胎发生期间，反义治疗 胚胎具有特定的损失或减少神经衍生的骨骼 元素，模仿CD患者观察到的颅面缺陷的方面。 我们的假设是转录因子SOX9是必不可少的成分 信号级联导致神经rest形成。我们建议：1） - 通过定义的时间来表征神经rest中的Sox9活动 Sox9对神经rest形成的需求。 2） - 确定Sox9是否 特定的神经rest谱系需要活动，通过靶向SOX9 在神经褶皱区域的耗尽，形成颅骨或躯干 波峰衍生物。 3） - 定义信号的起源和性质 调节神经褶皱中的Sox9表达。 CD患者异常的频谱表明 Sox9在性别确定和骨骼发展中，但在 其他发展过程。这里提出的工作将解决该功能 信号级联中的Sox9导致神经rest形成。