Molecular and cellular functions of the alternatively spliced isoforms of GDNF receptor complex in neuronal differentiation

Abstract

GDNF and NTN are currently in clinical trials for Parkinson?s disease. This thesis investigated the hypotheses that combinatorial interactions of GDNF/NTN, GFRa and co-receptor isoforms result in diverse biological functions through activations of distinct signaling pathways involving proteins, mRNAs and microRNAs. The cAMP-PKA signaling was found to be essential for GFL function and underlies differential neuritogenic activities of GFRa2 isoforms. Unexpectedly, specific interactions of GFRa2c and RET9 induced STAT3-serine727 phosphorylation and mitochondrial localization, illustrating a hitherto unrecognized mechanism in mediating neurite outgrowth. Furthermore, high performance assays and integrated workflows were developed for accurate quantifications of microRNAs and mRNAs, which led to the discovery of the distinct regulations and functions of GFRa and co-receptor isoforms during neurogenesis. These findings further highlighted the diverse functions of GDNF ligand receptor system and provided novel insights into the underlying signaling mechanisms that allowed a single ligand to exert a plethora of biological effects.