Pax62/2 Mice Have a Cell Nonautonomous Defect in Nonradial Interneuron Migration

The mammalian neocortex comprises two major neuronal subtypes; interneurons derived from the ganglionic eminence (GE) and projection neurons from the cortical ventricular zone (VZ). These separate origins necessitate distinct pathways of migration. Using mouse genetics and embryonic forebrain slice culture assays, we sought to identify substrates and/or guidance molecules for nonradial cell migration (NRCM). Mice carrying a mutation in Pax6 (Sey2/2), a paired domain transcription factor, are reported to have increased numbers of cortical inhibitory interneurons, sug-gesting that Pax6 could induce inhibitors of interneuron develop-ment or alternatively play a repressive role in guiding NRCM and/or specifying interneurons. Unexpectedly, we found a cell nonauton-omous reduction in the distance Sey2/2 neurons migrated, reflect-ing a disorganized migration, with frequent changes in direction. In contrast, no difference in the number of nonradially migrating GE cells was observed in Sey2/2 mice. Our data indicate that the increased numbers of interneurons observed in Sey2/2 do not result from an increased rate or number of nonradially migrating cells; instead, loss of Pax6 results in the ectopic specification of interneurons in the cortical VZ. Further, our data indicate that the known axonal disorganization in Sey2/2 mice contributes to the observed reduced distance of NRCM