miR-9 Controls the Timing of Neurogenesis through the Direct Inhibition of Antagonistic Factors

The timing of commitment and cell-cycle exit within progenitor populations during neurogenesis is a fundamental decision that impacts both the number and identity of neurons produced during development. We show here that microRNA-9 plays a key role in this process through the direct inhibition of targets with antagonistic functions. Across the ventricular zone of the developing zebrafish hindbrain, miR-9 expression occurs at a range of commitment stages. Abrogating miR-9 function transiently delays cell-cycle exit, leading to the increased generation of late-born neuronal populations. Target protection analyses in vivo identify the progenitor-promoting genes her6 and zic5 and the cell-cycle exit-promoting gene elavl3/HuC as sequential targets of miR-9 as neurogenesis proceeds. We propose that miR-9 activity generates an ambivalent progenitor state poised to respond to both progenitor maintenance and commitment cues, which may be necessary to adjust neuronal production to local extrinsic signals during late embryogenesis. ► miR-9 expression encompasses several progenitor commitment states ► miR-9 sets the timing of cell-cycle exit in neuronal progenitors ► miR-9 sequentially inhibits antagonistic targets, including her6/zic5 and elavl3 ► miR-9 activity leads to the emergence of an ambivalent progenitor state Coolen et al. show that microRNA-9 sequentially inhibits antagonistic targets, including her6/zic5 and elavl3, during neurogenesis progression. This activity generates an ambivalent progenitor state that can integrate local proliferation and differentiation cues and sets the timing of cell-cycle exit during late embryogenesis.