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Specific microRNAs modulate ES cell-derived neurogenesis

MicroRNAs (miRNAs) are recently discovered small non-coding transcripts with a broad spectrum of functions described mostly in invertebrates. As post-transcriptional regulators of gene expression, miRNAs trigger target mRNA degradation or translational repression. While hundreds of miRNAs have been cloned from a variety of mammalian tissues and cells, and multiple mRNA targets have been predicted, little is known about their functions. So far, a role of miRNA has only been described in hematopoietic, adipocytic and muscle differentiation, regulation of insulin secretion and potentially of cancer growth. Here, we describe miRNA expression profiling in mouse embryonic stem (ES) cell-derived neurogenesis in vitro and show that a number of miRNAs are simultaneously co-induced during differentiation of neural progenitor cells to neurons and astrocytes. There was a clear correlation between miRNA expression profiles in ES cell-derived neurogenesis in vitro and in embryonal neurogenesis in vivo. Using both gain-of-function and loss-of-function approaches, we demonstrate that brain specific miR-124a and miR-9 molecules affect neural lineage differentiation in the ES cell-derived cultures. In addition, we provide evidence that STAT3, a member of the signal transducer and activator of transcription (STAT) family pathway, is involved in the function of these miRNAs. We conclude that distinct miRNAs play a functional role in the determination of neural fates in ES cell differentiation.