REVIEW Otx Genes and the Genetic Control of Brain Morphogenesis

Understanding the genetic mechanisms that control brain patterning in vertebrates represents a major challenge for developmental neurobiology. The cloning of genes likely to be involved in the organization of the brain and an analysis of their roles have revealed insights into the molecular pathways leading to neural induction, tissue specification, and regionalization of the brain. Among these genes, both Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd ) gene, contribute to several steps in brain morphogenesis. Recent findings have demonstrated that Otx2 plays a major role in gastrulation and in the early specification of the anterior neural plate while Otx1 is mainly involved in corticogenesis, and Otx1 and Otx2 genes cooperate in such a way that a minimal level of OTX proteins are required for proper regionalization and subsequent patterning of the developing brain. Finally, experiments have shown functional equivalence between Drosophila otd and vertebrate Otx genes, suggesting a surprising conservation of function required in brain development throughout evolution. The adult brain consists of a number of regions and subregions that are characterized by diverse cell types deriving from a neuroepithelial sheet of cells in the embryo. During brain development, distinct regions in this cell layer are specified following a precise patterning mechanism conferring to different cell types the appropriate regional identity (reviewed in Rubenstein et