Investigating the cellular and molecular mechanisms by which YPEL regulates synaptic function in Drosophila
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Authors
Wei, Tianlu
Issue Date
2025
Type
Dissertation
Language
en_US
Keywords
Alternative Title
Abstract
The Yippee-like (YPEL) gene family is evolutionarily conserved across species, from yeast to humans. It consists of five members: YPEL1 through YPEL5. The high degree of conservation among YPEL genes across diverse species suggests that they serve important biological functions. Various studies have shown that YPEL proteins are involved in processes ranging from cellular senescence to tissue development. Previous studies suggest that YPEL plays a role in nervous system function; however, the underlying cellular and molecular mechanisms remain poorly understood. In Chapter 2, we demonstrate that mutations in YPEL result in defects in neuromuscular junction development. We further demonstrate that YPEL negatively regulates p62 puncta formation in both motor and sensory neurons without altering total p62 protein levels. Notably, reduced p62 gene dosage significantly alleviates NMJ defects. Moreover, we discovered that reducing CncC activity in Drosophila fully rescues the neuromuscular junction defects caused by the YPEL mutation. CncC is the Drosophila ortholog of mammalian Nrf2, which functions as a transcription factor that regulates the stress responses, particularly oxidative stress. In addition, we observed that loss of YPEL function reduces reactive oxygen species levels in motor neurons. Collectively, these findings uncover a novel cellular and molecular mechanism underlying synaptic development, in which YPEL regulates NMJ formation through the p62-Nrf2 antioxidant pathway in Drosophila.
In Chapter 3, we demonstrate that YPEL physically interacts with F-box protein FBXL2, a component of the Skp1-Cullin-F-box ubiquitin ligase complex, responsible for substrate recognition and plays a crucial role in the ubiquitin-proteasome pathway. We demonstrate that mutations in FBXL2 lead to neuromuscular developmental defects. Notably, double mutations of YPEL and FBXL2 do not produce additive NMJ defects, suggesting that they function in a common pathway. Furthermore, similar to YPEL, FBXL2 negatively regulates p62 puncta formation in neurons, and reducing p62 gene dosage in the FBXL2 mutant background ameliorates the NMJ defects. Collectively, these findings suggest that YPEL regulates neuromuscular junction development by interacting with FBXL2 to modulate p62 dynamics.