Role of a Novel microRNA in Adult Neurogenesis.

Abstract

Multipotent, self-renewing stem cells which are present throughout the developing nervous system remain in discrete regions of the adult brain. In the subventricular zone (SVZ) signaling molecules, including the bone morphogenetic proteins and their secreted inhibitor, Noggin appear to play a critical role in controlling neural stem cell (NSC) behavior. To examine the function of this signaling pathway in the intact nervous system, we have developed a transgenic mouse model in which Noggin expression can be induced specifically in NSC via a Nestin promoter-driven reverse tetracycline-controlled transactivator (rtTA). In adult animals, induction of Noggin expression promotes proliferation of NSC in the SVZ, and shifts the differentiation of NSC from mature astrocytes to transit amplifying cells and oligodendrocyte precursor cells without depleting the NSC population. Interestingly, over-expression of Noggin in the adult SVZ neural stem cells also inhibits the expression of a novel microRNA-410 (miR-410). miR-410 is expressed in the developing nervous system, remaining in the germinal zones of the adult brain. Over-expression of miR-410 in SVZ derived neurospheres consistently inhibited neuronal and oligodendrocyte differentiation while promoting the formation of astrocytes. Conversely, inhibition of miR-410 activity in NSC promoted neuronal and decreased astroglial differentiation. In addition, over-expression of miR-410 rescued the increase in neuronal differentiation and the decrease in astroglial differentiation caused by Noggin over-expression. Using computer prediction algorithms and luciferase reporter assays, we identified multiple neurogenic genes including Elavl4 as one of the downstream targets of miR-410 via the canonical miRNA-3’UTR interaction. Over-expression of Elavl4 transcripts without the endogenous 3’ UTR rescued the decrease in neuronal differentiation caused by miR-410 over-expression. Interestingly, we also observed that miR-410 affected neurite morphology. Over-expression of miR-410 resulted in the formation of short, unbranched neurites. These results demonstrate that miR-410 controls the crucial lineage choice of adult neural stem cells between neurons and glial cells by controlling the expression of neurogenic genes, and suggest a method to regulate NSC differentiation following disease, injury or aging.