Regulatory mechanisms of cerebellar lineage development

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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 Atoh1 expression is dynamically controlled by H3K27 epigenetic signatures at the Atoh1 enhancer, with Insm1 as a key transcriptional repressor disrupting the Atoh1 autoregulatory loop and cell cycle progression, and enabling GC lineage differentiation. This hypothesis will be tested by determining (1) the epigenetic mechanism of Atoh1 expression and GC lineage differentiation, (2) Insm1 function and regulatory landscape during GC lineage development, and (3) the contribution of Insm1 in Atoh1 protein stability and GC lineage progression.