FOREBRAIN PATTERNING DEFECTS IN SMALL EYE MUTANT MICE

Pax6 is a member of the Pax gene family of transcriptional regulators that exhibits a restricted spatiotemporal expression in the developing central nervous system, eye and nose. Mutations in Pax6 are responsib le for inherited malformations in man, rat and mouse. To evaluate the role of Pax6 in forebrain development, we studied in detail mouse Smal l eye/Pax6 mutant brains. This analysis revealed severe defects in for ebrain regions where Pax6 is specifically expressed. The establishment of some expression boundaries along the dorsoventral axis of the seco ndary prosencephalon is distorted and the specification of several ven tral structures and nuclei is abolished. Specifically, the development of the hypothalamo-telencephalic transition zone and the ventral thal amus is distorted. Our detailed analysis included a comparison of the expression of Pax6, Dlx1 and several other genes during embryonic mous e brain development in wild-type and in the mutant Small eye (Sey) bra in, The results from the analysis of normal brain development show tha t the restricted expression of Pax6 and Dlx1 at E12.5 dpc respect doma ins within the forebrain, consistent with the implications of the pros omeric model for the organisation of the forebrain (L. Puelles and J. L. R. Rubenstein (1993) Trends Neurosci. 16, 472-479). Furthermore, we found an early restriction of Pax6 and Dlx1 expression into presumpti ve histogenetic fields that correlate with the formation of distinct f orebrain structures and nuclei. Our results are discussed in light of changes in adhesive properties in the Sey brain that might control seg regation, assembly and cell migration of progenitors of specific foreb rain regions.