Otx genes in brain morphogenesis

Abstract

Most of the gene candidates for the control of developmental programmes that underlie brain morphogenesis in vertebrates are the homologues of Drosophila genes coding for signalling molecules or transcription factors. Among these, the orthodenticle group includes the Drosophila orthodenticle (otd) and the vertebrate Otx1 and Otx2 genes, which are mostly involved in fundamental processes of anterior neural patterning. These genes encode transcription factors that recognise specific target sequences through the DNA binding properties of the homeodomain. In Drosophila, mutations of otd cause the loss of the anteriormost head neuromere where the gene is transcribed, suggesting that it may act as a segmentation "gap" gene. In mouse embryos, the expression patterns of Otx1 and Otx2 have shown a remarkable similarity with the Drosophila counterpart. This suggested that they could be part of a conserved control system operating in the brain and different from that coded by the HOX complexes controlling the hindbrain and spinal cord. To verify this hypothesis a series of mouse models have been generated in which the functions of the murine genes were: (i) fully inactivated, (ii) replaced with each others, (iii) replaced with the Drosophila otd gene. Otx1-/- mutants suffer from epilepsy and are affected by neurological, hormonal, and sense organ defects. Otx2-/- mice are embryonically lethal, they show gastrulation impairments and fail in specifying anterior neural plate. Analysis of the Otx1-/-; Otx2+/- double mutants has shown that a minimal threshold level of the proteins they encode is required for the correct positioning of the midbrain-hindbrain boundary (MHB). In vivo otd/Otx reciprocal gene replacement experiments have provided evidence of a general functional equivalence among otd, Otx1 and Otx2 in fly and mouse. Altogether these data highlight a crucial role for the Otx genes in specification, regionalization and terminal differentiation of rostral central nervous system (CNS) and lead to hypothesize that modification of their regulatory control may have influenced morphogenesis and evolution of the brain.