Molecular Genetics of Early Neurogenesis

描述（申请人的描述）：细胞在细胞分裂期间彼此通信。 开发以创建用于建立 不同的细胞命运相对少量的不同信号系统 在细胞内聚合以改变预先存在的转录活性 因子，以组合方式结合顺式作用增强子元件 并调控下游靶基因的表达。相比 会聚信号转导途径和整合增强子元件， 在接收细胞内的功能，相对较少的是知道如何 信号传导在受体活化之前被细胞外控制。重点 这个提议的一个重要目的是了解果蝇的各种形式的Sog 在发育过程中在细胞外调节BMP信号传导的蛋白质 胚胎神经和非神经外胚层和成年翅膀模式。 我们目前的初步数据表明，短原肠胚（sog）基因， 编码一个大的胞外蛋白（Sog），可以调节 骨形态发生蛋白（BMP）亚家族的不同成员， TGF-β配体，如十肢麻痹（Dpp）和玻璃底船（Gbb）。我们 分析表明，全长Sog蛋白是在一种细胞类型中加工的， 以特定方式产生不同形式的Sog， 由不同的BMP亚群介导。例如，Sog的截断形式 （Supersog）具有比完整Sog更宽的BMP抑制活性。类超声波 分子是在体内制造的，这种过程可以在体外重建， 通过将完整的Sog与金属蛋白酶Tolloid（Tld）和辅因子结合 这就是所谓的胃扭曲（Tsg）。实验的总体目标是 在本申请中提出的是理解 不同的Sog活动，分析了替代形式的机制， Sog的产生，并确定这些分子如何调节信号， 不同的BMP配体在短或长的范围。 该提案的具体目标是： 1)检验Tld + Tsg将Sog加工成Supersog的模型。 2)确定不同形式的Sog是否阻断了BMP的选定子集 配体。 3)分析Sog的积极作用形式并确定其作用范围。

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.