The human oncogene SCL/TAL1 interrupting locus is required for mammalian dopaminergic cell proliferation through the Sonic hedgehog pathway

The human oncogene SCL/TAL1 interrupting locus (Stil) is highly conserved in all vertebrate species. In humans, the expression of Stil regulates cancer cell proliferation and survival. In this study, we examined the function of Stil in neural progenitor cell proliferation and neural differentiation using the mammalian dopaminergic (DA) PC12 cells. Stil is expressed in both proliferating and differentiated PC12 cells. The RNAi-mediated knockdown of Stil expression yielded a decreased proliferation rate of PC12 cells, whereas the overexpression of Stil transcript increased PC12 cell proliferation. The up- and down-regulation of the Sonic hedgehog (Shh) pathway by pharmacological approaches targeting Smoothened (Smo) demonstrated that Stil functions in the Shh pathway for PC12 proliferation. Smo antagonist cyclopamine decreased the proliferation rate of PC12 cells, whereas the overexpression of Stil rescued the cyclopamine-induced decrease in cell proliferation. Oppositely, the application of Smo agonist purmorphamine increased the rate of PC12 cell proliferation. However, the proliferation defect caused by Stil knockdown remained evident after activating the Shh pathway by purmorphamine. The expression of Stil is not required for PC12 cell neural differentiation. In PC12 cells transfected with Stil shRNA plasmids, the outgrowth of neurites persisted after treatment with nerve growth factor (NGF), whereas overexpression of Stil did not increase neurite growth in response to NGF induction. Together, the results from this study suggest a novel role for the oncogene Stil in neural progenitor cells through the Shh pathway, and further introduces Stil as a bio-marker for DA cells.