[P1.17]: A role for activated H‐RAS in cortical development and costello syndrome

ATF5 is a bZIP transcription factor that is a member of the ATF/ CREB family. Recent studies have indicated a role for ATF5 in neural, astrocyte and oligodendrocyte progenitor proliferation. Studies done in vivo and in vitro indicate that ATF5 promotes neuroprogenitor cell proliferation and that down-regulation of ATF5 is necessary for such cells to exit the cell cycle and differentiate. Furthermore, expression of ATF5 is high in glioblastomas where its expression appears to be required for survival. Though existing data shed light on biological functions of ATF5, there is little information regarding mechanisms that govern the induction and maintenance of ATF5 expression in proliferating neuroprogenitors and in tumor cells. Because of its well characterized properties, we chose the developing mouse cerebellum as a model system to address these issues. ATF5 protein is highly expressed by cerebellar granule neuron progenitors (GNPs) in the EGL and expression diminishes as GNPs differentiate into granule neurons. Such expression coincides with regions of Sonic Hedgehog (Shh)-driven proliferative activity in the EGL. We therefore assessed in GNP cultures whether ATF5 might be under the control of Shh, a major GNP mitogen. Without added Shh, both ATF5 expression and GNP proliferation rapidly fell. In Shh-treated cultures, in contrast there was a robust increase in the proportion of ATF5 positive cells. Childhood medulloblastomas are thought to arise largely from GNPs and examination of a number of such tumors revealed high expression of ATF5. In summary, our in vivo and in vitro observations are consistent with the idea that ATF5 plays a required role in cerebellar neuroprogenitor cell proliferation and suggest that Shh signaling is involved in ATF5 regulation in this population. Our findings also suggest a potential role for ATF5 in medulloblastomas.