Selector genes, limb identity and laterality in vertebrates

Early in the development of the embryo the primary axes are defined morphol ogically ana at the molecular level. The recent discovery of vertebrate hom eodomain-containing transcription factors related to drosophila bicoid has revealed that many of these factors play a role in specification of identit y for large embryonic fields. Whereas Otx2 was previously shown to confer i dentity to the most rostral neuroepithelium and has been postulated to play a role in the head organizer function, the recently identified genes Pitx1 and Pitx2 behave as determinants of posterior and left lateral plate mesod erm, respectively. Pitx1 thus appears to be at the head of a regulatory cas cade for specification of hindlimb identity. This cascade includes Tbx4, a brachyury-related gene, expressed only in hindlimbs in contrast to the rela ted Tbx5 gene which appears to play a similar role in forelimbs. Pitx2 is u niquely expressed in the left lateral plate mesoderm and appears to be the transcriptional effector for development of asymmetric internal organs such as the heart, stomach, intestine and lungs. Its expression in the left lat eral plate mesoderm is under stringent control of a regulatory cascade that has been best defined in chicken. The discovery of the Pitx genes has prov ided the first molecular insight into the mechanisms for the development of non-symmetrical structures in vertebrates.