Date of Award
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biology
First Advisor
Alicia M. Ebert
Abstract
Cell communication underlies all the processes critical to organismal development. Cell growth, survival, and migration would not be possible if not for signaling, and the molecules that allow propagation of those signals. One class of signaling proteins, the SH2 and SH3 domain-containing adaptors, are crucial for coupling the action of upstream tyrosine phosphorylation events to downstream effectors. This induces a wide variety of growth factor and extracellular matrix signals in a large array of cellular contexts in development. As arguably one of the most complex tissues formed during development, the central nervous system is no exception to this reliance on cell communication. In fact, one family of SH2 and SH3 domain-containing adaptors, CRK and CRKL, are critical for structure formation of the cortex, cerebellum, and hippocampus in the central nervous system in mice. These structures are all highly laminated, or layered, and therefore rely on neuronal migration, mediated by CRK adaptor signaling, for patterning. These are not the only laminated structures in the central nervous system – the neuronal retina is also a highly layered structure whose formation relies on migration, but the signaling mechanisms involved are poorly understood. Recently, a large body of literature has emerged suggesting that redundancy in the genome plays a bigger role during development than originally anticipated. Interestingly, there are four families of SH2 and SH3 domain-containing adaptor proteins, like CRK adaptors, in the vertebrate proteome, yet a direct comparison of functional redundancy between these similar proteins has never been performed. I hypothesized that if any SH2 and SH3 domain-containing adaptors were involved in retinal development, then maybe multiple overlapping adaptors could be. In this study, I aimed to elucidate the roles of Crk adaptors in the development of the vertebrate retina. As zebrafish are both a great model to study retinal development, and genetic and functional redundancy mechanisms, I utilized them for this work. Through the discovery of Crk and Crkl’s critical roles in retinal structure formation, I found evidence suggesting they are not the only proteins involved. To discover proteins with overlapping functions, I utilized bioinformatics and proteomics to investigate common signaling capabilities between CRK and another similar SH2 and SH3 domain-contain adaptor family, NCK. Finally, I elucidated Nck adaptor’s roles in the development of the zebrafish retina and compared them to Crk adaptor’s roles in the same system. Through this work, I found evidence suggesting that Crk and Nck share synergistic roles in zebrafish retinal development, possibly through overlapping signaling mechanisms. Importantly, this work adds to the growing body of research suggesting that developmental signaling mechanisms are more robust due to evolutionary fail-safes in the form of redundantly functioning proteins.
Language
en
Number of Pages
242 p.
Recommended Citation
Stergas, Helaina Renee, "Compensatory Mechanisms in Eye Development: Critical overlapping roles of Crk and Nck adaptor proteins in the zebrafish retina" (2024). Graduate College Dissertations and Theses. 1811.
https://scholarworks.uvm.edu/graddis/1811