Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Greg J. Bashaw

Abstract

Frazzled (Fra) is a highly conserved receptor expressed on the cell membrane, and it is important for several morphological processes, including cell migration, axon guidance, and adhesion. In addition to these functions, the vertebrate homologue of Fra, Dcc, also functions as a tumor suppressor that has a pro-apoptotic effect in the absence of its canonical ligand Netrin. In both invertebrates and vertebrates, the axon guidance cue Netrin interacts with the extracellular domain of Fra/Dcc to recruit cytoplasmic proteins and affect local cytoskeletal changes to promote axon growth across the midline. In addition, Fra functions independently of Netrin as a transcription factor. Fra is cleaved by gamma-secretase, which allows the Fra intracellular domain to enter the nucleus and activate transcription. Fra activates transcription of Commissureless, and endosome cycling receptor that is required to promote axon growth across the midline. However, whether this signaling mode of Fra is required in other tissue contexts outside of the nervous system is unknown. In Chapter 1, I introduce a subset of axon guidance genes and how they regulate gene expression in the nervous system as well as their known roles in reproductive tissues. In Chapter 2, I show that Fra is required in the fly ovary for egg chambers to progress through mid-oogenesis independently of Netrin, and this requires the transcriptional activation domain within the Fra intracellular domain. Interestingly, in contrast to the pro-apoptotic role that Dcc has in vertebrates, Fra has an anti-apoptotic role in the germline. In Chapter 3, I use a yeast-two hybrid screen to identify proteins that interact with the Fra intracellular domain, and test the DNA-binding proteins identified for a role in axon guidance and in the female germline. Finally, in Chapter 4 I discuss the implications of this work and potential future directions that would be exciting to explore.

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