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Theses Doctoral

Integration of EGFR and LIN-12/Notch signaling in Vulval Precursor Cell fate specification in Caenorhabditis elegans

Underwood, Ryan

Cellular differentiation is the cornerstone of metazoan development. Cell-cell signaling mechanisms are responsible for the specification of many cell fates. The response of a particular cell to a given signal is highly context dependent allowing signaling mechanisms to be reused to produce a variety of different outcomes. The EGFR and LIN-12/Notch signaling pathways are well-conserved across metazoan species and govern many fate-specification events. The specification of C. elegans Vulval Precursor Cells (VPCs) offers a powerful system to investigate how these signaling mechanisms specify cell-fates, and previous studies of VPC fate patterning have identified several forms of crosstalk between these two critical signaling mechanisms. In this thesis, I investigate how input from both the EGFR and LIN-12/Notch signaling pathways is integrated by the VPCs. I provide evidence that VPCs respond to the relative levels of LIN-12/Notch and EGFR signaling. I show that LIN-1/Elk1 is critical for VPCs to adopt discrete cell fates. In addition, I show that the Mediator components SUR-2/Med23 and the CDK-8 kinase module (CKM), in cooperation with LIN-1/Elk1, are required for an EGFR-mediated resistance to LIN-12/Notch activity. I also used CRISPR/Cas9 techniques to generate endogenous, fluorescently-tagged LAG-1 proteins. Characterization of tagged LAG-1 accumulation in the VPCs and in the somatic gonad show that LAG-1 is present in all VPCs at low levels in a lin-12/Notch independent manner. Activation of LIN-12/Notch is correlated with higher levels of LAG-1 accumulation compared to cells that do not have activated LIN-12/Notch. These findings suggest a potential autoregulation mechanism for lag-1 in certain contexts. They also suggest that endogenously tagged LAG-1 may be a useful molecular marker of LIN-12/Notch activation.

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More About This Work

Academic Units
Biochemistry and Molecular Biophysics
Thesis Advisors
Greenwald, Iva S.
Degree
Ph.D., Columbia University
Published Here
April 6, 2018