Emx2 directs the development of diencephalon in cooperation with Otx2

The vertebrate brain is among the most complex biological structures of whi ch the organization remains unclear. Increasing numbers of studies have acc umulated on the molecular basis of midbrain/hindbrain development, Set rela tively little is known about forebrain organization, Nested expression amon g Otx and Emx genes has implicated their roles in rostral brain regionaliza tion, but single mutant phenotypes of these genes have not provided suffici ent information. In order to genetically determine the interaction between Emx and Otx genes in forebrain development, we have examined Emx2(-/-)Otx2( -/-) double mutants and Emx2 knock-in mutants into the Otx2 locus (Otx2(div ided by /Emx2)). Emx2(-/-)Otx2(+/-) double mutants did not develop dienceph alic structures such as ventral thalamus, dorsal thalamus/epithalamus and a nterior pretectum. The defects were attributed to the loss of the Emx2-posi tive region at the three- to four-somite stage, when its expression occurs in the laterocaudal forebrain primordia, Ventral structures such as the hyp othalamus, mammillary region and tegmentum developed normally. Moreover, do rsally the posterior pretectum and posterior commissure were also present i n the double mutants. In contrast, Otx2(+/Emx2) knock-in mutants displayed the majority of these diencephalic structures; however, the posterior prete ctum and posterior commissure were specifically absent. Consequently, devel opment of the dorsal and ventral thalamus and anterior pretectum requires c ooperation between Emx2 and Otx2, whereas Emx2 expression is incompatible w ith development of the commissural region of the pretectum.