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The transcription factor REST is a key suppressor of neuronal genes in non-neuronal tissues. REST has been shown to suppress proneuronal microRNAs in neural progenitors indicating that REST-mediated neurogenic suppression may act in part via microRNAs. We used neural differentiation of Rest-null mouse ESC to identify dozens of microRNAs regulated by REST during neural development. One of the identified microRNAs, miR-375, was upregulated during human spinal motor neuron development. We found that miR-375 facilitates spinal motor neurogenesis by targeting the cyclin kinase CCND2 and the transcription factor PAX6. Additionally, miR-375 inhibits the tumor suppressor p53 and protects neurons from apoptosis in response to DNA damage. Interestingly, motor neurons derived from a spinal muscular atrophy patient displayed depressed miR-375 expression and elevated p53 protein levels. Importantly, SMA motor neurons were significantly more susceptible to DNA damage induced apoptosis suggesting that miR-375 may play a protective role in motor neurons.

Original publication

DOI

10.1002/stem.2233

Type

Journal article

Journal

Stem Cells

Publication Date

01/2016

Volume

34

Pages

124 - 134

Keywords

CCND2, Motor neuron, PAX6/REST, miR-375, Animals, Apoptosis, Base Sequence, Humans, Mice, MicroRNAs, Molecular Sequence Data, Motor Neurons, Muscular Atrophy, Spinal, Nerve Degeneration, Neurogenesis, Signal Transduction, Tumor Suppressor Protein p53