Regulatory mechanisms of cerebellar lineage development

PROJECT SUMMARY Granule cells (GCs) constitute over 95% of the cerebellar volume. They receive and integrate sensory, motor, and non-sensorimotor signals to fine-tune motor behaviors and cognitive tasks. GCs are generated from transiently proliferating granule cell precursors (GCPs) over a long time extending from early embryonic period until first postnatal year in human. Accordingly, cerebellar hypoplasia is one of the most common brain complications in premature infants with poor developmental outcomes. We have very limited basic knowledge of how GC lineage is established. Our long term goals are to elucidate the regulatory mechanisms of GC lineage development, and to understand how different risk factors cause cerebellar hypoplasia. A master regulator of GCP development is the bHLH transcription factor Atoh1 that maintains the GCP fate through activation of its own expression. This autoregulatory feedback loop is further supported by a cell cycle regulator Ccnd1 that stabilizes Atoh1 protein from degradation. However, it remains unclear as to how Atoh1 and Ccnd1 expressions are terminated to enable timely progression from GCPs to GCs. Our preliminary data suggest that Sin3A, a component of histone deacetylase (Hdac)–containing transcriptional corepressor complex, is essential for GCP differentiation by epigenetically silencing Atoh1 expression. We have also identified Insm1, a zinc-finger transcription factor, as a potential partner of the Sin3A-Hdac complex that inhibits Atoh1 and Ccnd1 expression. Based on these and other preliminary observations, we propose the novel hypothesis that the Sin3a/Hdac/Insm1 complex epigenetically represses Atoh1 and Ccnd1 expression, thereby integrating transcriptional and posttranslational signals to regulate GCP fate and cell cycle progression. This hypothesis will be tested by establishing (1) Sin3A function during GC lineage development, and (2) the role of Insm1 in GCP differentiation.