Text

theses

Members of the transforming growth factor β (TGFβ) superfamily function in a compelling array of developmental processes. This family of secreted ligands, as well as the signal transduction pathway, are highly conserved across metazoan biology. Due to this high level of conservation, the work described in this dissertation utilizes C. elegans as a genetic model organism to further elucidate fundamental mechanisms of TGFβ signaling. The Sma/Mab pathway, a conserved TGFβ pathway, regulates diverse developmental programs such as body size and innate immunity, among others. We performed a microarray study to uncover a system wide analysis of how such diverse developmental programs are executed. Consistent with the regulation of body size by the pathway, genes involved in protein synthesis, degradation, and metabolism were upregulated by Sma/Mab signaling. In addition, genes involved in innate immunity were also positively regulated by the pathway. Transport of the TGFβ receptors from the plasma membrane to endosomes has been proposed to promote TGFβ signal transduction and shape ligand gradients throughout development. However, how the postendocytic trafficking of TGFβ receptors contributes to the regulation of signal transduction has remained enigmatic. In this study we set out to identify the molecular sorting complexes that regulate the TGFβ receptors’ recycling and to determine how receptor recycling affects signaling. Our in vivo results provide evidence that clathrindependent endocytosis is necessary for TGFβ signaling in C. elegans. Furthermore, we find that after internalization, two distinct recycling pathways regulate the transport of the type I and type II receptors back to the cell surface. Recycling of the type I receptor is regulated by the retromer complex, whereas the type II receptor is recycled via a distinct recycling pathway regulated by ARF-6. Genetic screens performed in our lab based on the Sma body size phenotype have uncovered several TGFβ signaling components. From this screen sma-10(wk88) has been characterized as a positive regulator of TGFβ signaling. I have shown that SMA-10 regulates the intracellular trafficking of the type I and type II TGFβ receptors. Furthermore, my studies show that SMA-10 localizes to both early and late endosomes.

ETD_5402

Ph.D.

Includes bibliographical references

by Ryan Joseph Gleason

doi:10.7282/T3N29V7K

ETD doctoral

The author owns the copyright to this work.