Molecular mechanisms modulating BMP signaling

描述（由申请人提供）：骨形态发生蛋白（Bone morphogenetic proteins， BMP）属于转化生长因子（TGF）配体超家族，BMP信号通路在多种发育和稳态过程中发挥作用。该通路的功能障碍导致人类许多躯体和遗传性疾病，包括心血管疾病和癌症。因此，在正确的细胞环境下，必须存在机制来确保BMP信号的适当时空控制。我们使用自由生活的线虫，秀丽隐杆线虫，作为模型系统来解剖体内调节BMP信号的分子机制。秀丽隐杆线虫具有丰富的遗传和分子工具以及整个谱系的可用性，为在单细胞分辨率下研究完整生物体发育过程中BMP信号的功能和调节提供了一个很好的模型系统。我们开发了一种新颖有效的遗传筛选方法，可以识别秀丽隐杆线虫中特异性调节bmp样Sma/Mab信号通路的因子。我们已经证明单个秀丽隐杆线虫RGM蛋白drag1在配体受体水平上积极调节Sma/Mab信号传导。我们还发现秀丽隐杆线虫的同源物UNC-40通过直接结合drag1来促进Sma/Mab信号传导，并且这种功能与其在轴突和细胞迁移中的功能是可分离的。我们的筛选还发现了保守的四联蛋白分子TSP-21和鞘糖脂（GSLs）在促进Sma/Mab信号传导中的作用，为富含四联蛋白的膜微域参与调节TGF -信号传导提供了第一个体内证据。最后，我们的突变体筛选也表明在Sma/Mab通路中存在额外的“新因子”。进一步鉴定相应的蛋白，并解剖这些蛋白在调节Sma/Mab信号传导中的作用机制，将为在体内发育的动物中调节BMP信号传导的分子机制提供重要的见解。它们也可能为BMP通路突变引起的不同疾病提供潜在的治疗靶点。

DESCRIPTION (provided by applicant): Bone morphogenetic proteins (BMPs) belong to the transforming growth factor � (TGF�) superfamily of ligands and the BMP signaling pathway plays roles in multiple developmental and homeostatic processes. Malfunction of the pathway causes many somatic and hereditary disorders in humans, including cardiovascular diseases and cancer. Thus mechanisms must exist to ensure proper spatiotemporal control of BMP signaling in the right cellular context. We are using the free-living nematode, C. elegans, as a model system to dissect the molecular mechanism modulating BMP signaling in vivo. C. elegans, with its wealth of genetic and molecular tools and the availability of the entire lineage, provides an excellent model system to study the functions and modulation of BMP signaling during the development of an intact organism at single cell resolution. We have developed a novel and efficient genetic screen that has allowed the identification of factors specifically modulating the BMP-like Sma/Mab signaling pathway in C. elegans. We have demonstrated that the single C. elegans RGM protein DRAG-1 acts at the ligand-receptor level to positively modulate Sma/Mab signaling. We have also discovered that the C. elegans neogenin homolog UNC-40 functions by directly binding to DRAG-1 to promote Sma/Mab signaling and that this function is separable from its function in axon and cell migration. Our screen has also uncovered a role for a conserved tetraspanin molecule TSP-21 and glycosphingolipids (GSLs) in promoting Sma/Mab signaling, providing the first in vivo evidence for the involvement of tetraspanins-enriched membrane microdomains in modulating TGF� signaling. Finally, our mutant screen also indicated the presence of additional "novel factors" functioning in the Sma/Mab pathway. Further identification of the corresponding proteins and mechanistic dissection on how these proteins function in modulating Sma/Mab signaling will provide important insights into the molecular mechanisms involved in regulating BMP signaling in developing animals in vivo. They may also provide potential therapeutic targets for the different diseases caused by mutations in the BMP pathway.