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Dissertation Information
Title: A Journey To The Center Of The Cell: The Characterization Of Novel Non-Canonical Mechanisms Of Notch Signaling
Program: Doctor of Philosophy in Biomolecular Sciences
Advisor: Dr. Allan Albig, Biological Sciences
Committee Members: Dr. Cheryl Jorcyk, Biological Sciences; Dr. Daniel Fologea, Physics; and Dr. Henry Charlier, Chemistry and Biochemistry
Abstract
Cellular signaling pathways are the main method of communication between cells throughout the body. Of the many complex signaling pathways, the Notch signaling pathway is an ancient, highly conserved pathway critical to most animal life. This pathway is not only able to respond to juxtracrine signals from neighboring cells, but also acts as a microenvironment sensor, allowing cells to react to a variety of situations. Thus, understanding the mechanisms behind the regulation of Notch signaling is crucial to improving our basic understanding of Notch in cell biology and development. This dissertation introduces two previously undescribed non-canonical regulatory mechanisms of the Notch signaling pathway: heterodimerization and biomolecular condensate formation. Although Notch1 homodimerization has been characterized, the details of interaction between the four Notch isoforms have yet to be fully explored. We found that not only do all four Notches heterodimerize, but that these interactions are transcriptionally relevant. The second non-canonical mechanism, condensate formation, has only begun to be discovered, with little research exploring Notch1 localization into non-membrane bound organelles. We have found that each Notch isoform differentially forms these biomolecular condensates, leaving much to be uncovered about their overall function. My work, as well as that of my colleagues, has begun to characterize an entirely new understanding of how Notch signaling works. Once thought to be a straightforward pathway, my contributions as a basic scientist have introduced a layer of complexity that will help to understand how Notch can perform a variety of functions.
