Otx genes are required for tissue specification in the developing eye

Patterning of the vertebrate eye appears to be controlled by the mutual reg ulation and the progressive restriction of the expression domains of a numb er of genes initially coexpressed within the eye anlage, Previous data sugg est that both Otx1 and Otx2 might contribute to the establishment of the di fferent eye territories. Here, we have analysed the ocular phenotype of mic e carrying different functional copies of Otx1 and Otx2 and we show that th ese genes are required in a dose-dependent manner for the normal developmen t of the eye. Thus, all Otx1(-/-); Otx2(+/-) and 30% of Otx1(+/-); Otx2(+/- ) genotypes presented consistent and profound ocular malformation, includin g lens, pigment epithelium, neural retina and optic stalk defects. During e mbryonic development, optic vesicle infolding was severely altered and the expression of pigment epithelium-specific genes, such as Mitf or tyrosinase , was lost. Lack of pigment epithelium specification was associated with an expansion of the prospective neural retina and optic stalk territories, as determined by the expression of Pax6, Six3 and Pax2, Later in development the presumptive pigment epithelium region acquired features of mature neura l retina, including the generation of Islet1-positive neurones, Furthermore , in Otx1(-/-) Otx2(+/-) mice neural retina cell proliferation, cell differ entiation and apoptotic cell death were also severely affected. Based on th ese findings we propose a model in which Otx gene products are required for the determination and differentiation of the pigment epithelium, co-operat ing with other eye patterning genes in the determination of the specialised tissues that will constitute the mature vertebrate eye.