Function of the Six and Eya Genes in Retinal Development

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Project Summary The early development of a number of insect and mammalian tissues including the eye requires the activity of an evolutionarily conserved regulatory circuit that includes members of the PAX, SIX, EYA and DACH gene families. Of particular interest to this proposal is the role that the SIX and EYA proteins play in the early formation and initial patterning of the retina. The function of these two gene families are highly significant to human health as mutations can lead to holoprosencephaly with associated cyclopia, bilateral anophthalmia and congenital cataracts as well as non-retinal defects such as myotonic dystrophy and branchio-oto-renal syndrome. Furthermore, these genes are also implicated in tumorigenesis and numerous cancers. SIX proteins are homeobox containing transcription factors whereas EYA proteins have transcriptional co-activator and protein tyrosine phosphatase activities. These proteins regulate the transcription of target genes as SIX-EYA heterodimers. Disruption of these complexes, in addition to causing retinal disorders in both mouse models and human patients, leads to a complete block in retinal development in Drosophila melanogaster. The fruit fly eye has become a premier model system for studying the genetic and molecular mechanisms that govern tissue determination. We will take advantage of the no-eye phenotypes caused by mutations in the sine oculis (so) and eyes absent (eya) genes (the founding members of the SIX and Eya gene families) to investigate novel activities of the So-Eya complex. The ability of this complex to also coax non-ocular tissue into adopting an eye fate (ectopic eyes) is another tool that can be utilized to dissect the roles that these proteins play in early retinal determination and patterning. In this application I propose to (1) study a novel mechanism by which the So-Eya complex represses transcription of non-ocular selector genes during early eye formation; (2) identify transcription factors that bind to and activate recently identified novel enhancers of the eya gene; and (3) determine the molecular and functional relationships between the So-Eya complex and the Decapentaplegic (Dpp) signaling pathway. The association of SIX and EYA gene lesions with retinal disorders in both insect and mammalian systems provides us with an exciting opportunity for studies in the Drosophila eye to advance our understanding of mammalian eye formation and human retinal disorders.