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.

Public Health Relevance

The BMP signaling pathway is important for multiple developmental and homeostatic processes. Malfunction of this pathway can lead to various disorders, including cardiovascular diseases and cancer. Identifying factors modulating BMP signaling and determining their mode of action in vivo will not only provide valuable insight into our general understanding of BMP signaling, but may also identify potential therapeutic targets for the different diseases caused by mutations in the pathway.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM103869-01A1
Application #
8630486
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Gaillard, Shawn R
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cornell University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850