All ETDs from UAB

Advisory Committee Chair

Rosa Serra

Advisory Committee Members

Chenbei Chang

Jianbo Wang

Susan Bellis

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cell to cell communication is fundamental to all life processes, from fertilization to death. The TGFߟ superfamily is a large family of proteins that is involved in a wide array of physiological and pathological processes, including development, wound healing, immune system function, cancer, and reproduction. This group of signaling peptides is well conserved across many organisms, from basic nematode to humans. While many studies have aimed to delineate the functions of TGFߟ, they have also unveiled the complexity of this multifunctional family of ligands. In this thesis, I take advantage of the simple C. elegans model system to study the function of TGFߟ, focusing specifically on the DAF-7 TGFߟ signaling pathway. DAF-7 is a TGFߟ homolog that functions through the classical Type I and Type II receptor complexes to phosphorylate downstream R-Smads. In the canonical DAF-7 pathway, phosphorylated R-Smads inhibit the Co-Smad DAF-3 to mediate downstream functions. The DAF-7 pathway was initially identified for its role in dauer formation. However, studies in the last few decades have provided insight into a whole host of functions that are regulated by this pathway, including fat accumulation, germ cell proliferation, chemoreceptor expression, and prostaglandin metabolism. To get a glimpse of the total direct and indirect genes that are regulated by the canonical DAF-7 TGFߟ pathway, we performed RNA sequencing of wild type, daf-1 Type I receptor, and daf-1;daf-3 double mutant hermaphrodites. Gene ontology analysis of the differentially expressed genes suggest that the canonical DAF-7 pathway also modulates processes such as response to topologically incorrect protein, response to biotic stimulus, and passive transmembrane transporter activity, in addition to known roles from targeted functional studies. Future studies should focus on targeted genetic and functional studies to provide more insight into the role of the TGFߟ pathway. In the second part of the thesis, I focus on the role of the DAF-7 pathway in reproduction in C.elegans, specifically its functions in modulating prostaglandin metabolism and sperm guidance. C.elegans synthesize a specific class of F-series prostaglandins that are important for guiding sperm to the oocyte. However, the enzyme (s) responsible for prostaglandin synthesis have yet to be identified. daf-1 mutants exhibit low prostaglandin levels that are correlated with poor sperm guidance. However, the mechanism is not well understood. In this thesis, I provide evidence showing that daf-1 modulates prostaglandin levels not by affecting the enzyme(s) that is responsible for its synthesis, but rather by inhibiting the ability of the enzyme(s) to access polyunsaturated fatty acid precursors, such as arachidonic acid (AA). Future studies should aim to identify the genes that are responsible for regulating AA availability and trafficking. Understanding these signaling mechanisms in C. elegans may offer further insight into human development and disease.

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