EQUIVALENCE OF THE FLY ORTHODENTICLE GENE AND THE HUMAN OTX GENES IN EMBRYONIC BRAIN-DEVELOPMENT OF DROSOPHILA

Members of the orthodenticle gene family are essential for embryonic b rain development in animals as diverse as insects and mammals. In Dros ophila, mutational inactivation of the orthodenticle gene results in d eletions in anterior parts of the embryonic brain and in defects in th e ventral nerve cord. In the mouse, targeted elimination of the homolo gous Otx2 or Otx1 genes causes defects in forebrain and/or midbrain de velopment. To determine the morphogenetic properties and the extent of evolutionary conservation of the orthodenticle gene family in embryon ic brain development, genetic rescue experiments were carried out in D rosophila, Ubiquitous overexpression of the orthodenticle gene rescues both the brain defects and the ventral nerve cord defects in orthoden ticle mutant embryos; morphology and nervous system-specific gene expr ession are restored. Two different time windows exist for the rescue o f the brain versus the ventral nerve cord. Ubiquitous overexpression o f the human OTX1 or OTX2 genes also rescues the brain and ventral nerv e cord phenotypes in orthodenticle mutant embryos; in the brain, the e fficiency of morphological rescue is lower than that obtained with ove rexpression of orthodenticle. Overexpression of either orthodenticle o r the human OTX gene homologs in the wild-type embryo results in ectop ic neural structures. The rescue of highly complex brain structures in Drosophila by either fly or human orthodenticle gene homologs indicat es that these genes are interchangeable between vertebrates and invert ebrates and provides further evidence for an evolutionarily conserved role of the orthodenticle gene family in brain development.