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Ubiquitin Proteasome System regulation of Retinal Development
The ubiquitin proteasomal system (UPS) is a highly selective post-translational mechanism which plays a role in a multitude of cellular processes including protein quality control, cell cycle control, proliferation, synaptic plasticity, transcriptional regulation, signal transduction and the development of several different tissues. It plays an important role in maintaining cellular homeostasis and is directly responsible for protein quality control check of oxidized, mutated, misfolded, denatured or unnecessary proteins. The UPS regulates many different biological processes and responds to changing physiological conditions and its mis-regulation is known to be associated with congenital disease, including visual impairment
E3 ubiquitin ligases, like Siah, bind to substrates targeting them for proteasome-mediated degradation using a common and conserved binding motif that acts as a degradation signal or ‘‘degron’’ motif. The Siah degron has been elucidated to encode the P-[ARTE]-x-V-x-P, with the core V-x-P constituting residues with highest conservation. Interestingly, a recent screen of the zebrafish proteome identified 2 potential vertebrate targets related to eye development, Nlz2 and Cdhr1a. Recent work in the lab has characterized mechanisms regulating both optic fissure fusion (nlz2) and photoreceptor development (cdhr1a) via Siah activity. Future studies aim to focus on Siah function in photoreceptor progenitor function, rod photoreceptor outer segment homeostasis as well as potential role during zebrafish photoreceptor regeneration.