Otx genes in brain morphogenesis

Most of the gene candidates for the control of developmental programmes tha t underlie brain morphogenesis in vertebrates are the homologues of Drosoph illa 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 fundam ental processes of anterior neural patterning. These genes encode transcrip tion factors that recognise specific target sequences through the DNA bindi ng properties of the homeodomain. In Drosophila, mutations of otd cause the loss of the anteriormost head neuromere where the gene is transcribed, sug gesting that it may act as a segmentation 'gap' gene. In mouse embryos, the expression patterns of Otx1 and Otx2 have shown a remarkable similarity wi th the Drosophila counterpart. This suggested that they could be part of a conserved control system operating in the brain and different from that cod ed by the HOX complexes controlling the hindbrain and spinal cord. To verif y this hypothesis a series of mouse models have been generated in which the functions of the murine genes were: (i) fully inactivated, (ii) replaced w ith each others, (iii) replaced with the Drosophila otd gene. Otx1 - / - mu tants suffer from epilepsy and are affected by neurological, hormonal, and sense organ defects. Otx2 - / - mice are embryonically lethal, they show ga strulation impairments and fail in specifying anterior neural plate. Analys is of the Otx1 - / -; Otx2 + / - double mutants has shown that a minimal th reshold level of the proteins they encode is required for the correct posit ioning of the midbrain-hindbrain boundary (MHB). In vivo otd/Otx reciprocal gene replacement experiments have provided evidence of a general functiona l equivalence among otd, Otx1 and Otx2 in fly and mouse. Altogether these d ata highlight a crucial role for the Otx genes in specification, regionaliz ation and terminal differentiation of rostral central nervous system (CNS) and lead to hypothesize that modification of their regulatory control may h ave influenced morphogenesis and evolution of the brain. (C) 2001 Elsevier Science Ltd. All rights reserved.