The cerebellum is critical for motor coordination and cognitive function. Granule neurons are a key component of cerebellar circuitry and are thought to represent the cell of origin for the pediatric brain tumor medulloblastoma. While the development of granule neurons has been studied in detail, the signals that control their growth and differentiation remain unclear. During postnatal development, proliferation of granule neuron precursors (GNPs) is driven by the mitogen Sonic hedgehog (Shh), which is produced from neighboring Purkinje cells. Interestingly, GNPs also proliferate during embryonic development, at a stage prior to Shh secretion;the mitogen responsible for this proliferation is unknown. Our preliminary studies indicate that a mitogenic activity is present in extracts from the embryonic cerebellum. Here we propose to identify this mitogen and study its role in cerebellar development. Specifically, we aim to (1) Use tissue microdissection and cell sorting to determine the source of the mitogen, and (2) Use expression cloning to identify the mitogen at a molecular level. These studies will not only provide insight into the mechanisms that control cerebellar development, but will also identify novel signaling pathways that may be important in medulloblastoma formation.
Identifying the signals that control production of neurons in the cerebellum may have important implications for understanding diseases in which cerebellar structure and function are impaired, including ataxia and autism. In addition, since signals that control growth and differentiation are often dysregulated in cancer, these studies may shed light on the etiology of cerebellar tumors such as medulloblastoma.
