In recent years it has become apparent that the genetic networks specifying cell-fate are conserved across species. Interestingly, these regulatory cassettes are also deployed in multiple developmental contexts, for example in the morphogenesis of different organs. An excellent example of this is the Eyeless - Eyes Absent - Sine oculis - Dachshund cascade originally described in fly eye development, and called the retinal determination pathway. An analogous pathway is involved in vertebrate eye and muscle development, and components of the network have been implicated in brain, ear, and kidney development. Mutations in these genes are associated with several human developmental diseases including bronchio-oto-renal syndrome and congenital cataracts (Eyes Absent), holoprosencephaly, bilateral anophtalmia and pituitary anomalies (mutations in the human sine oculis genes), aniridia (mutations in Pax6, the human homologoue of Eyeless), as well as postaxial polydactyly type A2, mental retardation, and a form of Bardet-Biedel syndrome (Dachshund mutations). It is our long-term goal to unravel the molecular mechanisms underlying these regulatory pathways. This proposal focuses on the two novel protein families in this network: Eyes Absent and Dachshund. ? ? We have recently obtained evidence that Eyes Absent has protein tyrosine phosphatase activity and that Dachshund contains a DNA-binding motif. These unexpected observations alter existing models for the roles of these two critical retinal determination proteins, and are the basis for the studies proposed here. We plan to use crystallography and biochemistry in an integrated effort to decipher the molecular mechanisms of Eyes Absent and Dachshund action during early embryonic development. ? ?
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