Control of neural crest development in Xenopus

描述(申请人提供)：SOX蛋白属于一大类 转录因子与SRY相关，是睾丸的决定因子。表达式 在胚胎发育过程中，这些蛋白质在特定的细胞类型中似乎控制着 细胞命运的决定。这个家族的一名成员，老鼠Sox9，已经被证明 通过结合和激活软骨细胞特异性调节软骨形成 II型胶原增强剂(Col2a1)。与这一角色一致，Col2a1和 SOX9在所有成软骨前体细胞中均有共表达。Sox9结果中的突变 在驼峰发育不良(CD)中，一种以XY性别为特征的致死性人类疾病 反转和严重的骨骼畸形。在胚胎发育过程中，SOX 9也是 在神经脊祖细胞中表达。CD患者也存在缺陷 起源于神经沟的颅面骨骼元素(腭部和颌部) 提示Sox9可能在脑神经脊区起重要作用 队形。 初步研究表明，SOX9是形成神经峰所必需的 在非洲爪哇发育过程中。Sox9是在原肠胚期表达的 神经隆起形成区。在这个组织中，Sox9在空间上是共定位的 在时间上带有鼻涕虫，已知是最早被激活的基因 神经波峰诱导信号。在发育中的胚胎中消耗Sox9，使用一个 新的反义方法，导致神经脊前体细胞的丢失和 神经组织扩张。在胚胎发育的后期，反义治疗 胚胎有一种特定的神经脊衍生骨骼的丢失或减少 元素，模拟CD患者观察到的头面部缺陷的方面。 我们的假设是转录因子Sox9是一个必不可少的成分 导致神经峰形成的信号级联。我们建议：1)-至 通过定义时间来表征SOX9在神经脊内的活动 SOX9对神经峰形成的要求。2)-确定Sox9是否 通过以Sox9为靶点，特定的神经脊谱系需要活动 神经折叠区的耗竭，注定会形成颅骨或躯干 CREST衍生品。3)-定义信号的来源和性质 调节神经皱折中Sox9的表达。 CD患者的异常谱系表明， Sox9在性别决定和骨骼发育中也发挥着重要作用 其他发育过程。这里提出的工作将解决该功能 Sox9在导致神经峰形成的信号级联中的作用。

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.