Nf2-dependent regulation of neuronal scaling in the developing cerebellum

总结

Summary The production of different types of neurons in the appropriate proportions, called neuronal scaling, is critical for the formation of functional neural circuits and proper excitatory/inhibitory balance. Disruption of neuronal scaling contributes to the pathogenesis of developmental brain disorders, including spinocerebellar ataxia and autism. Although significant progress has been made toward understanding the differentiation of specific neurons, little is known regarding the mechanisms that scale the number of functionally related neurons in the brain. The cerebellum contains only few neuronal cell types, the developmental origins of which are well- established. Thus, the cerebellum is an ideal system to study the mechanisms of neuronal scaling. In the cerebellum, both rhombic lip-derived excitatory granule neurons and ventricular zone-derived inhibitory interneurons are scaled relative to Purkinje cells, the only output neurons from the cerebellar cortex. Purkinje cells control the number of granule cells by secreting the Sonic hedgehog (Shh) protein, which promotes the proliferation of granule cell precursors and the expansion of progenitors in the prospective white matter (pWM) that give rise to inhibitory interneurons. Before migrating to the pWM, neural progenitors proliferate in the cerebellar ventricular zone (cVZ), which also gives rise to Purkinje cell layer progenitors (PCLPs), which during normal development produce exclusively glia. While Shh production by Purkinje cells and Shh transduction in granule cell precursors has been studied intensively, the neuronal scaling mechanisms that act intrinsically in cVZ-derived cells are poorly understood. In our preliminary studies, we found that loss of the Neurofibromatosis 2 (Nf2) gene results in a unique phenotype with disrupted scaling of both granule cells and inhibitory interneurons relative to Purkinje cells. Excitingly, our conditional knockout analysis in mice revealed that Nf2 controls neuronal scaling in the cerebellum acting intrinsically in cVZ-derived cells to regulate several distinct, poorly understood developmental steps. This proposal will characterize the molecular mechanisms that regulate neuronal scaling in the cerebellum, using Nf2 as an entry point, in three complementary Aims. In Aim 1, we will investigate how Nf2 coordinates the proliferation and migration of progenitors in the cVZ, identifying novel Nf2 downstream targets that regulate each of these processes. In Aim 2, we will define an Nf2-dependent pathway that regulates the expansion and proliferative response to Shh of pWM progenitors. In Aim 3, we will identify Nf2-dependent mechanisms that inhibit the misspecification of PCLPs into granule cells, preventing the production of excessive granule cells during normal development. Our studies will identify basic mechanisms that regulate development of the cerebellum, a major center of motor coordination and cognitive functions, will provide novel insights into human cerebellar developmental disorders, and help the development of brain regeneration therapies.