MiR-375 is Essential for Human Spinal Motor Neuron Development and May Be Involved in Motor Neuron Degeneration.
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.
Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore, Singapore.
Akshay
A
Bhinge
Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore, Singapore.
Seema C
SC
Namboori
Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London, UK.
Angela
A
Bithell
Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London, UK.
Chiara
C
Soldati
Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford, United Kingdom.
Noel J
NJ
Buckley
Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore, Singapore.|Department of Biological Sciences, National University of Singapore, Singapore, Singapore.|School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Lawrence W
LW
Stanton
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology*; D055495:Neurogenesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53
CCND2; Motor neuron; PAX6/REST; miR-375