Characterization of a BMP negative regulator, LON-2, in the extracellular matrix

Abstract

The conserved Bone Morphogenetic Protein (BMP) pathway impacts on a myriad of developmental processes in animals through the receptor relay molecules that target nuclear genes expression. In C. elegans, this pathway uses the ligand, DBL-1, to control the body length. This study investigated the negative regulatory control of this pathway with a focus on the glypican, LON-2. lon-2 antagonizes dbl-1 which is required for proper body length development in the worm. dbl-1 controls the body length through the Sma/Mab pathway that impacts on endoreduplication. lon-2 is expressed throughout the life cycle but its expression during the larval stage is sufficient for its control of body length. Study of the growth of lon-2 mutant revealed that LON-2 activity is required during the late larval stage and early adult hood. Ectopic expression of lon-2 shows that lon-2 is able to work non-autonomously. However, the rescue results indicate that lon-2 function is confined within locales proximal to where dbl-1 is expressed. Features of LON-2 molecule suggest that LON-2 works in the extracellular matrix. I show that the secretion of LON-2 is essential for its biological activity, and the presence of GPI linkage might be required for the attenuation of LON-2 release from the membrane. Neither the soluble or membrane anchored form of LON-2 could fully present its activity in vivo. Conserved interaction domains of LON-2 were not required for its regulation on the worm’s body length. Truncation study of LON-2 suggests that the entire core protein of LON-2 is required for its biological activity. LON-2 could have regulated DBL-1 in the ECM through physical binding between LON-2 and DBL-1 in the late larval stage for attenuation of BMP signal. Whether LON-2 competes with the receptor for ligand binding or it serves as a diffusion inhibitor is yet to be addressed.

Date of Award	2013
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology