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Characterization of the physiological role of adaptor protein ShcD in the adult mammalian central nervous system and testes

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Title: Characterization of the physiological role of adaptor protein ShcD in the adult mammalian central nervous system and testes
Author: Robeson, Hannah
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Jones, Nina
Abstract: Cellular signaling is an essential process by which an organism is able to interpret and respond to stimuli, eliciting responses which regulate important cellular functions including proliferation, differentiation, migration, and survival. These signaling cascades are mediated by protein-protein interactions which enable signal transduction, culminating in a biological response. Adaptor proteins, including those in the Shc (Src homology and collagen) family, are an important class of molecules involved in these pathways, functioning as scaffolds in the formation of signaling complexes. The Shc family constitutes four members – ShcA, -B, -C and -D – which share a similar general architecture but diverge in their expression profiles and specific functions. ShcD, the most recently identified Shc family member, remains the least well characterized. Though advancements have been made in identifying roles for ShcD in cancer pathology with links to metastasis, little remains known as to its roles in normal physiological signaling. Through a combination of in vitro, in vivo and in silico approaches, and the use of both cell-based and animal models, we provide a characterization of ShcD expression and function in two distinct organ systems with high ShcD expression – the brain and the testes. We first show that ShcD is expressed in both neural progenitor cells and mature neurons. We further demonstrate that knockout of ShcD in mice results in brain abnormalities including altered olfactory bulb morphology and function, as well as changes in biochemical signaling molecules associated with neuronal differentiation. This loss of ShcD results in alterations in cell populations in neurogenic niches, identifying a putative role for ShcD in neurogenesis. We also expanded our investigation to profile ShcD expression in the testes and identified marked ShcD expression in Sertoli cells. We demonstrate that overexpression of ShcD results in dysregulation of MAPK signaling pathways as well as alterations in proliferation. Finally, we show that overexpression of ShcD results in increased cellular outgrowth from a spheroid, suggesting ShcD may increase propensity for migration or alter cell-cell attachment. Together, these findings explore ShcD expression and function in a previously overlooked capacity and provide additional context for our understanding of this elusive molecule.
Date: 2022-09
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
Related Publications: Robeson HN, Lau HR, New LA, Lalonde J, Armstrong JN, Jones N. 2019. Localization of the phosphotyrosine adaptor protein ShcD/SHC4 in the adult rat nervous system. BMC Neuroscience. 20:57. doi: 10.1186/s12868-019-0541-5
Embargoed Until: 2023-09-06

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