2. Retinal Specification and Development

The Drosophila compound eye provides a powerful model system in which to study cross-talk between signal transduction networks and tissue specific transcriptional regulators. The stereotyped and repetitive architecture of the ~800 unit eyes or ommatidia and the sophisticated molecular genetic methodologies available together facilitate quantitative analysis of even minor perturbations to the underlying signaling networks. In addition, the dispensability of the organ for viability or fertility enables one to manipulate and study essential signaling processes specifically in the eye without globally perturbing development of the animal.

Intimately integrated within an elaborate web of signaling pathways important for eye development is the so-called “retinal determination (RD) network”. The RD network consists of a group of evolutionarily conserved transcription factors and cofactors that include Twin of eyeless (Toy), Eyeless (Ey), Eyes absent (Eya), Sine oculis (So) and Dachshund (Dac), with the mammalian counterparts referred to as Pax6 (homolog of both Toy and Ey), Eya, Six and Dach, respectively. Extensive genetic analyses have revealed the importance of interactions between the RD genes and other signaling pathways in regulating numerous facets of retinal development, including eye fate specification, proliferative versus differentiative choices, terminal differentiation and cell survival.

Our laboratory initially began studying Eya as a point of cross-talk between the RD network and the RTK signaling pathway. In the course of these investigations, we discovered that in addition to its relatively well-characterized role as a transcription factor, Eya also functions as a protein tyrosine phosphatase. Each of these functions is required for Drosophila eye development and perturbation of either activity leads to developmental abnormalities in humans. While some progress has been made towards understanding the transcriptional functions of Eya, neither the cellular and developmental processes in which Eya’s phosphatase activity participates nor the molecular mechanisms underlying its regulation and coordination with transcriptional functions have been elucidated. To address these questions, current studies in the lab seek to:

1. Identify the phosphotyrosine signaling pathways in which Eya operates as a phosphatase.
2. Identify physiological substrates of Eya phosphatase activity
3. Understand the relative contributions of transcriptional and phosphatase functions to critical events in retinal specification and development.

Related Publications

1.	Jemc J, Rebay I. Identification of transcriptional targets of the dual-function transcription factor/phosphatase eyes absent. Dev Biol. 2007 Oct 15;310(2):416-29.
2.	Jemc J, Rebay I. The eyes absent family of phosphotyrosine phosphatases: properties and roles in developmental regulation of transcription. Annu Rev Biochem. 2007;76:513-38. Review.
3.	Mutsuddi M, Chaffee B, Cassidy J, Silver SJ, Tootle TL, Rebay I. Using Drosophila to decipher how mutations associated with human branchio-oto-renal syndrome and optical defects compromise the protein tyrosine phosphatase and transcriptional functions of eyes absent. Genetics. 2005 Jun;170(2):687-95.
4.	Rebay I, Silver SJ, Tootle TL. New vision from Eyes absent: transcription factors as enzymes. Trends Genet. 2005 Mar; 21(3):163-71. Review.
5.	Tootle TL, Siver SJ, Davies EL, Newman V, Latek RR, Mills IA, Selengut JD, Parlikar BE, Rebay I. The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature. 2003 Nov 20;426(6964):299-302.
6.	Silver SJ, Davies EL, Doyon L, Rebay I. Functional dissection of eyes absent reveals new modes of regulation within the retinal determination gene network. Mol. Cell Biol. 2003 Sep;23(17):5989-99.