Snail1 contributes to Sonic Hedgehog pathway mediated proliferation and transformation of neural cells

Activation of the Sonic Hedgehog (Shh) pathway and increased expression of the Gli1 transcription factor have been implicated in the tumorigenesis of both sporadic and syndromic medulloblastoma, a malignant pediatric brain tumor that arises from cerebellar granule cell progenitors (GCPs). While Shh pathway activity is required for normal neural stem cell proliferation, molecular mechanisms of Shh pathway dysregulation and transformation of neural precursor cells remain poorly defined. I have identified Snail1 (Sna1) as a putative target of Gli1 in neural progenitor cells. I hypothesize that Sna1 participates in the transduction of Shh/Gli signaling in the cerebellum and plays a role in proliferation of neuronal progenitor cells in the cerebellum. In support of this hypothesis, I demonstrate that Sna1 is induced in GCPs by both ligand-mediated and genetic Shh pathway activation. Furthermore, Sna1 is directly induced by Shh signaling in human medulloblastoma cells and its expression is correlated to Gli1 induction in murine medulloblastoma lesions. Sna1 functions to induce proliferation of both GCPs and medulloblastoma cells, ultimately promoting in vitro transformation of human medulloblastoma cells. Analysis of potential Sna1 targets reveals that N-Myc protein is directly induced by Snail1 overexpression, thereby mediating Sna1-mediated proliferation and transformation. These data reveal that Sna1 has the capacity to function as a transcriptional activator in addition to its canonical role in transcriptional repression. My results support both unique and conserved roles for Sna1 in the proliferation and transformation of neural tissue, garnering critical insight into the mechanism of Shh-induced proliferation of neural progenitors through sequential activation of the Sna1 and N-Myc oncogenes.