Opposing Gradients of MicroRNA Expression Temporally Pattern Layer Formation in the Developing Neocortex

The precisely timed generation of different neuronal types is a hallmark of development from invertebrates to vertebrates. In the developing mammalian neocortex, neural stem cells change competence over time to sequentially produce six layers of functionally distinct neurons. Here, we report that microRNAs (miRNAs) are dispensable for stem-cell self-renewal and neuron production but essential for timing neocortical layer formation and specifying laminar fates. Specifically, as neurogenesis progresses, stem cells reduce miR-128 expression and miR-9 activity but steadily increase let-7 expression, whereas neurons initially maintain the differences in miRNA expression present at birth. Moreover, miR-128, miR-9, and let-7 are functionally distinct; capable of specifying neurons for layer VI and layer V and layers IV, III, and II, respectively; and transiently altering their relative levels of expression can modulate stem-cell competence in a neurogenic-stage-specific manner to shift neuron production between earlier-born and later-born fates, partly by temporally regulating a neurogenesis program involving Hmga2. [Display omitted] •Dicer is dispensable for neural stem-cell self-renewal and neuron production•Temporally opposite gradients of miR-128/9 and let-7 can time layer formation•miR-128, miR-9, and let-7 are functionally distinct in specifying laminar fates•miR-128 and miR-9 can reverse time-dependent neural stem-cell competence The mammalian neocortex has six layers of distinct neurons generated sequentially during embryogenesis by stem cells that change competence in producing specific neuronal types as neurogenesis progresses. Shu et al. show miR-128, miR-9, and let-7 form temporally opposite and functionally antagonistic expression/activity gradients to time changes in stem-cell competence.