LOCAL-CONTROL OF GRANULE CELL GENERATION BY CEREBELLAR PURKINJE-CELLS

Cerebellar Purkinje cells were ablated by the specific expression of d iphtheria toxin in these cells in transgenic mice. Purkinje cell degen eration during early postnatal development shows a zonally restricted pattern which has been exploited in order to look for local secondary effects. The most obvious early effect is the alignment of gaps in the Purkinje cell layer with dramatically thinned zones in the overlying EGL, the germinal layer from which granule cells are generated. Within these EGL zones in the transgenic mutant, markers that distinguish ma trix from mantle cells demonstrate a preferential loss of the prolifer ative cells. Comparison of BrdU incorporation in the mutant vs wild-ty pe confirms the reduction in proliferation. In the mutant, in situ lab eling of DNA fragmentation associated with apoptotic cell death shows abundant labeling of granule cells that have exited the EGL, but not o f progenitor cells in the EGL. Thus, although a trophic role for Purki nje cells has been well documented, these observations further suggest a mitogenic role which can be exerted locally.