Mechanism of MASH1 induction by ASK1 and ATRA in adult neural progenitors.

The molecular mechanisms underlying differentiation and lineage commitment in neural stem cells are just beginning to be understood, however the molecules involved in this process and their functions remain largely unknown. Here we studied the effects and downstream signals of apoptosis signal-regulating kinase 1 (ASK1) together with all-trans retinoic acid (ATRA) on neuronal differentiation in adult hippocampus-derived progenitor (AHP) cells. Following ASK1 over-expression and ATRA treatment in AHPs, a larger number of cells differentiated into neurons and the MASH1 promoter became activated. Analyzing downstream effector molecules of ASK1 or ATRA targeting the MASH1 promoter revealed that the myocyte enhancer factor 2C (MEF2C) mediated ASK1 signalling, while activation of Sp1 was involved in ATRA signalling. Chromatin immunoprecipitation assay on the promoter revealed that ASK1 induced binding of MEF2C and Ca(2+)/calmodulin-dependent kinase II to the MASH1 promoter. Taken together, ASK1 and ATRA activate MEF2C and Sp1, respectively, and up-regulate MASH1 protein expression.