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Deciphering the microRNA-mediated Control of Neural Stem Cell Function

Review of “MiRNA-137-mediated modulation of mitochondrial dynamics regulates human neural stem cell fate” from STEM CELLS by Stuart P. Atkinson

Recent research has revealed that pluripotency-associated factors control the expression of miR‐137 [1], a brain‐enriched micro (mi)RNA whose dysfunction has been linked to neurodevelopmental disorders [2, 3] and tumorigenesis. While data from mouse cells have suggested that miR‐137 influences neuronal differentiation and inhibits cell proliferation, the role of miR‐137 in human neural stem cells (NSCs) remained to be fully deciphered. In their recent STEM CELLS article, researchers led by Yogita K. Adlakha (Brain Research Centre, Manesar, India) investigated the role of miR‐137 in human NSCs [4], with their findings suggesting that miR‐137 can modulate NSC fate by altering mitochondrial dynamics [5].

Channakkar et al. first overexpressed miR‐137 in NSCs derived from induced pluripotent stem cells, finding an increase in proliferation, accelerated neuronal differentiation, and improved migratory capacity. To discover the mechanisms underlying the pro-neuronal influence of miR-137, the authors turned to in silico analysis to identify potential targets. Interestingly, the authors discovered that miR‐137 targeted the 3′untranslated region of myocyte enhancer factor‐2A (MEF2A) mRNA, which codes for a transcription factor that regulates peroxisome proliferator‐activated receptor‐gamma coactivator (PGC1α) transcription. Subsequent in vitro validation using a reporter assay confirmed that miR‐137 targets MEF2A in NSCs and that the miRNA-mediated down-regulation of MEF2A reduced the transcription of PGC1α and significantly impacted mitochondrial dynamics.

However, miR‐137 expression also accelerated mitochondrial biogenesis in a PGC1α-independent manner through the upregulation of both nuclear factor erythroid 2 (NFE2)‐related factor 2 (NRF2) and transcription factor A of mitochondria (TFAM). Additionally, the expression of miR‐137 also induced mitochondrial fusion and fission, leading to an increase in mitochondrial content, the activation of oxidative phosphorylation (OXPHOS), and an increase in oxygen consumption rate. Overall, this suggests that miR-137 can enhance neural differentiation of NSCs by modulating mitochondrial activity via several different mechanisms.

Of note, the authors also established that miR‐137 overexpression in NSCs prompted an increase in the levels of the OCT4 and SOX2 pluripotency-associated transcription factors. As the miR‐137 promoter also contains binding sites for OCT4 and SOX2, the authors suggest the existence of a feed‐forward self‐regulatory loop.

In this fascinating new study, the authors have shown that miR-137 enhances the neural differentiation of NSCs by modulating the mitochondria to match the metabolic/energetic requirements of the newly formed neurons. As the normal age-related decrease in neurogenesis associates with comprised regenerative abilities [6], the authors hope that their findings may lead to the development of novel approaches to battle the aging process and aid the treatment of neurodegenerative diseases.

For more on how microRNAs regulate stem cell activities, stay tuned to the Stem Cells Portal!

References

  1. Boyer LA, Lee TI, Cole MF, et al., Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells. Cell 2005;122:947-956.
  2. Willemsen MH, Vallès A, Kirkels LAMH, et al., Chromosome 1p21.3 Microdeletions Comprising DPYD and MIR137 are Associated with Intellectual Disability. Journal of Medical Genetics 2011;48:810.
  3. Strazisar M, Cammaerts S, van der Ven K, et al., MIR137 Variants Identified in Psychiatric Patients Affect Synaptogenesis and Neuronal Transmission Gene Sets. Molecular Psychiatry 2015;20:472-481.
  4. Channakkar AS, Singh T, Pattnaik B, et al., MiRNA-137-mediated modulation of mitochondrial dynamics regulates human neural stem cell fate. STEM CELLS 2020;38:683-697.
  5. Khacho M and Slack RS, Mitochondrial Dynamics in the Regulation of Neurogenesis: From Development to the Adult Brain. Developmental Dynamics 2018;247:47-53.
  6. Lledo P-M, Alonso M, and Grubb MS, Adult Neurogenesis and Functional Plasticity in Neuronal Circuits. Nature Reviews Neuroscience 2006;7:179-193.