MADS AND VERTEBRATE LIMB DEVELOPMENT

Mad(母亲抗十足瘫痪)基因家族被认为是 在细胞质信号转导中发挥关键作用 转化生长因子-β(TGF-β)配体家族。这块骨头 形态发生蛋白(BMP)是一种转化生长因子-β型配体，与 发育过程，包括图案化和分化 脊椎动物的肢体。这里提出的这项研究将解决这一角色 通过检测Mad蛋白在雏鸡肢体发育中的作用 人的异位表达(通过逆转录病毒介导的基因转移) MAD蛋白Smad1、Smad5和DPC4。显性否定和 这些蛋白质的成分激活形式也将进行测试。这个 Mad蛋白在BMP信号转导通路中的位置 通过检测野生型和突变型MADS抑制MADS的能力 骨形态发生蛋白的激活和显性阴性版本的影响 受体。最后，内源性MADS在糖尿病的发生发展中的作用 鸡胚胎肢体将通过克隆和鉴定得到确认 小鸡MADS的特征。这一特征将包括就地 杂交分析以及在胚胎肢体中的过表达 确认以前从人类MADS获得的表型。转化生长因子- β家族配体参与了细胞生长的调控， 而Mad基因DPC4和MADR2的丢失与 某些癌症。因此，研究Mad在生物中的作用 如本提案所述，背景将导致更大的 了解细胞生长和发育的控制，至关重要 肿瘤发生的过程。

The Mad (Mothers against decapentaplegic) gene family is thought to play a key role in the cytoplasmic transduction of signals from the transforming growth factor beta (TGF-beta) family of ligands. The bone morphogenetic proteins (BMPs) are TGF-beta type ligands implicated in developmental processes which include patterning and differentiation of the vertebrate limb. This research proposed here will address the role of Mad proteins in the developing chick limb by examining the effect ectopic expression (by retroviral mediated gene transfer) of the human Mad proteins Smad1, Smad5, and DPC4. Dominant negative and constitutively activated forms of these proteins will also be tested. The position of Mad proteins in the BMP signal transduction pathway will be tested by assaying the ability of wild-type and mutant Mads to suppress the effects of activated and dominant negative versions of the BMP receptor. Finally, the role of endogenous Mads in the development of the chick embryonic limb will be confirmed by the cloning and characterization of chick Mads. This characterization will include in situ hybridization analysis as well as overexpression in the embryonic limb to confirm the phenotypes previously obtained with human Mads. The TGF- beta family of ligands have been implicated in the control of cell growth, and loss of the Mad genes DPC4 and MADR2 has been associated with certain carcinomas. Therefore the study of Mad function in a biological context, as outlined in this proposal, will lead to a greater understanding of the control of cell growth and development, critical processes in the genesis of tumors.