Molecular mechanisms modulating BMP signaling

描述（由申请人提供）：骨形态发生蛋白（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，必须存在机制以确保在正确的细胞环境中对BMP信号传导进行适当的时空控制。我们使用自由生活的线虫C。elegans作为一个模型系统来剖析BMP信号在体内调节的分子机制。C. elegans以其丰富的遗传和分子工具以及整个谱系的可用性，提供了一个极好的模型系统，用于以单细胞分辨率研究完整生物体发育期间BMP信号传导的功能和调节。我们已经开发了一种新的和有效的遗传筛选，允许识别的因素，特别是调节BMP样Sma/Mab信号通路在C。优雅我们已经证明，单一的C。线虫RGM蛋白DRAG-1在配体-受体水平起作用以正向调节Sma/Mab信号传导。我们还发现C. elegans再生蛋白同源物β-40通过直接结合DRAG-1来促进Sma/Mab信号传导，并且该功能与其在轴突和细胞迁移中的功能是分开的。我们的筛选还揭示了保守的四跨膜蛋白分子TSP-21和鞘糖脂（GSL）在促进Sma/Mab信号传导中的作用，为四跨膜蛋白富集的膜微区参与调节TGF β信号传导提供了第一个体内证据。最后，我们的突变体筛选还表明了在Sma/Mab途径中存在额外的“新因子”。 进一步鉴定相应的蛋白质和机制解剖这些蛋白质如何在调节Sma/Mab信号转导将提供重要的见解参与调节BMP信号在体内发育的动物的分子机制。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.