Growth of the Developing Cerebral Cortex Is Controlled by MicroRNA-7 through the p53 Pathway

• The miR-7 sponge is sufficient to block silencing activity of three miR-7 precursors
• Cortical-specific miR-7 sponge transgenic mice show microcephaly-like brain defects
• Expansion and survival of cortical intermediate progenitors require miR-7 function
• miR-7 modifies expression levels of genes in the p53 pathway in the embryonic cortex

SummaryProper growth of the mammalian cerebral cortex is crucial for normal brain functions and is controlled by precise gene-expression regulation. Here, we show that microRNA-7 (miR-7) is highly expressed in cortical neural progenitors and describe miR-7 sponge transgenic mice in which miR-7-silencing activity is specifically knocked down in the embryonic cortex. Blocking miR-7 function causes microcephaly-like brain defects due to reduced intermediate progenitor (IP) production and apoptosis. Upregulation of miR-7 target genes, including those implicated in the p53 pathway, such as Ak1 and Cdkn1a (p21), is responsible for abnormalities in neural progenitors. Furthermore, ectopic expression of Ak1 or p21 and specific blockade of miR-7 binding sites in target genes using protectors in vivo induce similarly reduced IP production. Using conditional miRNA sponge transgenic approaches, we uncovered an unexpected role for miR-7 in cortical growth through its interactions with genes in the p53 pathway.

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