Molecular Genetics of Early Neurogenesis

早期神经发生的分子遗传学

• 批准号: 6729062
• 负责人: ETHAN BIER
• 金额: $ 38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729062
• 关键词: Drosophilidae; bone morphogenetic proteins; developmental genetics; developmental neurobiology; ectoderm; embryogenesis; enzyme activity; extracellular matrix proteins; gene mutation; invertebrate embryology; laboratory mouse; laboratory rabbit; laboratory rat; metalloendopeptidases; molecular genetics; neurogenesis; neurogenetics; transforming growth factors

DESCRIPTION (Applicant's Description): Cells communicate with each other during development to create positional information that is used to establish different cell fates. A relatively small number of distinct signaling systems converge within the cell to modify the activity of pre-existing transcription factors, which bind in a combinatorial fashion to cis-acting enhancer elements and regulate the expression of downstream target genes. In contrast to converging signal transduction pathways and integrating enhancer elements that function within the receiving cell, relatively little is known about how signaling is controlled extracellularly prior to receptor activation. The focus of this proposal is to understand how various forms of the Drosophila Sog protein function extracellularly to regulate BMP signaling during development of the embryonic neural and non-neural ectoderm and adult wing pattern. We present preliminary data indicating that the short gastrulation (sog) gene, which encodes a large extracellular protein (Sog), can modulate the activities of distinct members of the Bone Morphogenetic Protein (BMP) subfamily of TGF-beta ligands such as Decapentaplegic (Dpp) and Glass bottom boat (Gbb). Our analysis suggests that the full length Sog protein is processed in a cell-type specific fashion to generate different forms of Sog which block signaling mediated by distinct subsets of BMPs. For example, a truncated form of Sog (Supersog) has broader BMP inhibitory activity than intact Sog. Supersog-like molecules are made in vivo, and this processing can be reconstituted in vitro by combining intact Sog with the metalloprotease Tolloid (Tld) and a co-factor known as Twisted Gastrulation (Tsg). The overall goal of the experiments proposed in this application is to understand the developmental function of different Sog activities, analyze the mechanism by which alternative forms of Sog are produced, and determine how these molecules modulate signaling by different BMP ligands at short or long range. The Specific Aims of this proposal are: 1) Test the model that Tld plus Tsg processes Sog into Supersog. 2) Determine whether different forms of Sog block selected subsets of BMP ligands. 3) Analyze positive acting forms of Sog and determine their range of action.

描述(申请者的描述)：单元之间在 用于创建位置信息的开发，用于建立 不同的细胞命运。数量相对较少的不同信号系统 在细胞内收敛，以修改预先存在的转录的活性 以组合方式与顺式作用增强子元件结合的因子 并调控下游靶基因的表达。与之形成鲜明对比的是 汇聚信号转导通路和整合增强元件 在接收单元内起作用，人们对此知之甚少。 在受体激活之前，信号是在细胞外控制的。焦点 这一建议的目的是了解各种形式的果蝇SOG 蛋白质在发育过程中调节BMP信号的细胞外功能 胚胎的神经性和非神经性外胚层以及成体的翅膀图案。 我们提供的初步数据表明，短原肠形成(Sog)基因， 编码一种大的胞外蛋白(SOG)，可以调节活性 属于骨形态发生蛋白(BMP)亚家族的不同成员 转化生长因子-β配体，如十五面瘫(DPP)和玻璃底舟(GBB)。我们的 分析表明，全长的SOG蛋白是在一种细胞类型中加工的 生成阻止信令的不同形式的SOG的特定方式 由BMP的不同子集介导。例如，SOG的截断形式 (Supersog)比完整的SOG具有更广泛的BMP抑制活性。超级索格式 分子是在体内制造的，这个过程可以在体外重组 通过将完整的SOG与金属蛋白酶Tolloid(TLD)和辅助因子结合 称为扭曲原肠形成(TSG)。这些实验的总体目标是 在本应用程序中提出的目的是了解 不同的SOG活动，分析替代形式的SOG SOG的产生，并决定这些分子如何通过 短距离或长距离的不同BMP配体。 这项建议的具体目标是： 1)测试TLD+TSG将SOG处理成Supersog的模型。 2)确定不同形式的SOG是否阻止BMP的选定子集 配基。 3)分析SOG的积极作用形式，确定其作用范围。