Molecular mechanisms modulating BMP signaling

描述(申请人提供)：骨形态发生蛋白(BMP)属于转化生长因子�(转化生长因子�)超家族配体，骨形态发生蛋白信号通路在多种发育和动态平衡过程中发挥作用。该通路的功能障碍会导致人类许多躯体和遗传疾病，包括心血管疾病和癌症。因此，必须存在机制来确保在正确的细胞环境中对BMP信号进行适当的时空控制。我们正在使用自由生活的线虫，线虫，作为一个模型系统来剖析体内调控BMP信号的分子机制。线虫凭借其丰富的遗传和分子工具以及整个谱系的可获得性，为在单细胞分辨率下研究完整生物体发育过程中BMP信号的功能和调控提供了一个很好的模型系统。我们已经开发了一种新颖而有效的遗传筛选，它可以识别线虫中特定调控BMP样Sma/Mab信号通路的因子。我们已经证明了单个线虫RGM蛋白Drag-1在配体-受体水平上作用于正向调节Sma/Mab信号。我们还发现线虫新生素同系物UNC-40通过直接与Drag-1结合来促进Sma/Mab信号转导而发挥功能，并且这一功能与其在轴突和细胞迁移中的功能是分开的。我们的筛查还发现了一个保守的TSP-21分子和神经鞘糖脂(GSLs)在促进Sma/Mab信号转导中的作用，为富含THPA的膜微域参与调节转化生长因子�信号提供了第一个体内证据。最后，我们的突变筛选还表明，在Sma/Mab途径中存在其他起作用的“新因子”。进一步鉴定相应的蛋白质，并对这些蛋白质如何调节Sma/Mab信号的机制进行剖析，将为了解体内发育中动物BMP信号调节的分子机制提供重要的见解。它们还可能为BMP途径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.