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

Affiliation

The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China. Electronic address: [Email]

Abstract

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.

Keywords

cortical lamination,layer formation in the neocortex,microRNA,neural-stem-cell competence,temporal patterning during neurogenesis,

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