The genetic networks specifying cell-fate are largely conserved across species. Interestingly, the same 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 (SIX) - Dachshund cascade originally described in fly eye development - the retinal determination (RD) pathway involved in vertebrate eye and muscle development, with components of the network also implicated in brain, ear, and kidney development. Mutations in these genes are associated with several human developmental diseases including branchio-oto-renal syndrome (eyes absent), holoprosencephaly, bilateral anophthalmia and pituitary anomalies (mutations in the human sine oculis genes (the SIX genes)), aniridia (mutations in PAX6, the human homologue of eyeless), as well as postaxial polydactyly type A2, intellectual disability, and a form of Bardet-Biedl syndrome (Dachshund mutations). It is our long-term goal to unravel the molecular mechanisms underlying these regulatory pathways using structural biology, solution and cellular biochemistry.

Work in our laboratory has shown that:

  • Eyes absent proteins are protein tyrosine phosphatases (PTP). This unexpected finding was important for two reasons: first it demonstrated for the first time that the RD pathway, rather than being a purely transcriptional cascade, was also involved in signal transduction. And second, the eyes absent proteins are the prototype for a new mechanistic class of protein tyrosine phosphatases that do not contain the signature Cys-containing motif previously considered diagnostic of PTPs.
  • The phosphatase activity of eyes absent is associated with increased cell motility, invasiveness, and transformation – all hallmarks of transformed cells with metastatic potential.
  • Interaction between the SIX and EYA proteins results in significant changes in their activities; the phosphatase activity of Eya3 as well as the DNA-binding affinity of Six2 is increased.
  • We have determined the crystal structure of the most conserved region of Dachshund and shown that it contains a winged-helix DNA binding domain.