| Summary: | Each cell in a developing organism undergoes a defined sequence of developmental events to reach its final functional state. At decision points along their path to terminal differentiation, cells interpret a subset of the available instructions encoded by the genome to select the correct developmental trajectory. Molecularly, combinations of transcription factors initiate and stabilize these cellular decisions by activating context-specific gene expression program. Thus, understanding how transcription factors are regulated to generate diverse developmental outcomes is a fundamental challenge in biology.
The master regulatory retinal determination gene network (RDGN) is a classic model to study how transcription factors direct organogenesis. Members of this network choreograph proliferation, specification, differentiation, and morphogenesis to shepherd cells through the entire sequence of retinal development in Drosophila. Two RD proteins, Eyes absent (Eya) and Sine oculis (So), form a composite transcription factor that regulates all of these cellular processes. Recent work reveals that the Eya-So complex can activate or repress transcription of target loci depending on context, but the molecular mechanisms that confer specificity and flexibility to its transcriptional output are unknown.
In this dissertation, I explore how Eya-So activity is controlled to coordinate cellular behaviors during retinogenesis. Chapter 1 argues that rewiring of regulatory interactions within the RDGN underlies this network's ability to direct the deterministic sequence of eye development. In Chapter 2, I describe the results of a screening strategy that uncovered dozens of novel Eya-binding proteins, many of which likely serve as co-factors for the Eya-So complex. Chapter 3 investigates how one hit from this screen, the transcription factor Combgap, antagonizes Eya-So's transcriptional activity to coordinate the cell cycle with other developmental processes in the eye. This work also established a new role for Eya-So in scheduling cell cycle exit in retinal precursor cells. In Chapter 4, I present evidence that Eya's tyrosine phosphatase activity is important for its function in vivo. Finally, Chapter 5 places these results in the context of our current understanding of how the RDGN directs eye development and proposes key future experiments. Together, these investigations suggest that precise regulation of Eya-So activity contributes to its function as a master regulator of retinal development.
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