| The subventricular zone (SVZ) is the largest neurogenic niche in the adult mammalian brain. Stem cells in this region are SVZ astrocytes, glial cells classically associated with support functions. A key question is how stem cells with glial characteristics transition along the lineage into neurons. Here I show that microRNAs (miRNAs) are important regulators whose key role in stem cell biology is just emerging. One of these miRNAs, the brain-enriched miR-124, is an important regulator of the timing of SVZ stem cell lineage progression. Knockdown of endogenous miR-124 maintains SVZ stem cells as dividing precursors, whereas ectopic expression leads to precocious neuron formation. Furthermore, miR-124 expression is required during SVZ neuronal regeneration. I identify the SRY-box transcription factor Sox9 and the DED-domain protein PEA-15 to be physiological targets of miR-124 in the adult mouse SVZ. Sox9 mRNA, but not protein, is present in SVZ neuroblasts. Blocking endogenous miR-124 leads to ectopic Sox9 protein expression in neuroblasts. Sox9 overexpression abolished neuronal differentiation whereas Sox9 knockdown led to increased neurogenesis and decreased glial formation. Thus, the dynamic interplay between miRNAs and their targets, demonstrated by miR-124 and Sox9 here in this dissertation, is important for progression along the SVZ stem cell lineage into neurons. |
