Differential transcriptional control as the major molecular event in generating Otx1-/- and Otx2-/- divergent phenotypes

Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) ge ne, show a limited amino acid sequence divergence, Their embryonic expressi on patterns overlap in spatial and temporal profiles with two major excepti ons: until 8 days post coitum (d,p,c.) only Otx2 is expressed in gastrulati ng embryos, and from 11 d.p,c, onwards only Otx1 is transcribed within the dorsal telencephalon. Otx1 null mice exhibit spontaneous epileptic seizures and multiple abnormalities affecting primarily the dorsal telencephalic co rtex and components of the acoustic and visual sense organs. Otx2 null mice show heavy gastrulation abnormalities and lack the rostral neuroectoderm c orresponding to the forebrain, midbrain and rostral hindbrain, In order to define whether these contrasting phenotypes reflect differences in expressi on pattern or coding sequence of Otx1 and Otx2 genes, we replaced Otx1 with a human Otx2 (hOtx2) full-coding cDNA, Interestingly, homozygous mutant mi ce (hOtx2(1)/hOtx2(1)) fully rescued epilepsy and corticogenesis abnormalit ies and showed a significant improvement of mesencephalon, cerebellum, eye and lachrymal gland defects, In contrast, the lateral semicircular canal of the inner ear was never recovered, strongly supporting an Otx1-specific re quirement for the specification of this structure. These data indicate an e xtended functional homology between OTX1 and OTX2 proteins and provide evid ence that, with the exception of the inner ear, in Otx1 and Otx2 null mice contrasting phenotypes stem from differences in expression patterns rather than in amino acid sequences.