Specific MicroRNAs Modulate Embryonic Stem Cell–Derived Neurogenesis

Anna Krichevsky

Kai Sonntag

Ole Isacson

Kenneth Kosik

^{Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA}

^{Center for Neuroregeneration Research, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA}

^{Neuroscience Research Institute, University of California-Santa Barbara, Santa Barbara, California, USA}

Correspondence: Anna M. Krichevsky, Ph.D., 4 Blackfan Circle, HIM 760, Boston, Massachusetts 02115, USA. Telephone: 617-525-5195; Fax: 617-525-5305; e-mail: ude.dravrah.hwb.dnc@yksvehcirk; and Kai-C. Sonntag, M.D., Ph.D., 115 Mill Street, Belmont, Massachusetts 02478, USA. Telephone: 617-855-3138, Fax: 617-855-3284; e-mail: ude.dravrah.naelcm@gatnnos.iak

Abstract

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. Although 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 regulation 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 signal transducer and activator of transcription (STAT) 3, a member of the 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.

Keywords: Embryonic stem cells, MicroRNA array, MicroRNA, Neurogenesis

Abstract

Footnotes

Disclosures The authors indicate no potential conflicts of interest.

Footnotes

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