miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche
Li-Chun Cheng, Erika Pastrana, Masoud Tavazoie, Fiona Doetsch, Li-Chun Cheng, Erika Pastrana, Masoud Tavazoie, Fiona Doetsch
Abstract
The subventricular zone (SVZ) is the largest neurogenic niche in the adult mammalian brain. We found that the brain-enriched microRNA miR-124 is an important regulator of the temporal progression of adult neurogenesis in mice. Knockdown of endogenous miR-124 maintained purified SVZ stem cells as dividing precursors, whereas ectopic expression led to precocious and increased neuron formation. Furthermore, blocking miR-124 function during regeneration led to hyperplasias, followed by a delayed burst of neurogenesis. We identified the SRY-box transcription factor Sox9 as being a physiological target of miR-124 at the transition from the transit amplifying cell to the neuroblast stage. Sox9 overexpression abolished neuronal differentiation, whereas Sox9 knockdown led to increased neuron formation. Thus miR-124-mediated repression of Sox9 is important for progression along the SVZ stem cell lineage to neurons.
Figures
References
- Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999;97:703–716.
- Menn B, et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci. 2006;26:7907–7918.
- Lachapelle F, Avellana-Adalid V, Nait-Oumesmar B, Baron-Van Evercooren A. Fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor AB (PDGF AB) promote adult SVZ-derived oligodendrogenesis in vivo. Mol Cell Neurosci. 2002;20:390–403.
- Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297.
- Stefani G, Slack FJ. Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol. 2008;9:219–230.
- Flynt AS, Lai EC. Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nat Rev Genet. 2008;9:831–842.
- Lagos-Quintana M, et al. Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002;12:735–739.
- Lim LP, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433:769–773.
- Conaco C, Otto S, Han JJ, Mandel G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:2422–2427.
- Krichevsky AM, Sonntag KC, Isacson O, Kosik KS. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells. 2006;24:857–864.
- Makeyev EV, Zhang J, Carrasco MA, Maniatis T. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Molecular Cell. 2007;27:435–448.
- Visvanathan J, Lee S, Lee B, Lee JW, Lee SK. The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes & Development. 2007;21:744–749.
- Cao X, Pfaff SL, Gage FH. A functional study of miR-124 in the developing neural tube. Genes & Development. 2007;21:531–536.
- Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR. Neurons derived from radial glial cells establish radial units in neocortex. Nature. 2001;409:714–720.
- Haubensak W, Attardo A, Denk W, Huttner WB. Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:3196–3201.
- Pastrana E, Cheng L-C, Doetsch F. Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. Proceedings of the National Academy of Sciences of the United States of America, in press. 2009
- Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, Alvarez-Buylla A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron. 2002;36:1021–1034.
- Lim DA, Alvarez-Buylla A. Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:7526–7531.
- Malatesta P, Hartfuss E, Gotz M. Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development. 2000;127:5253–5263.
- Meister G, Landthaler M, Dorsett Y, Tuschl T. Sequence-specific inhibition of microRNA-and siRNA-induced RNA silencing. RNA. 2004;10:544–550.
- Hutvagner G, Simard MJ, Mello CC, Zamore PD. Sequence-specific inhibition of small RNA function. PLoS Biology. 2004;2:E98.
- Davidson TJ, et al. Highly efficient small interfering RNA delivery to primary mammalian neurons induces MicroRNA-like effects before mRNA degradation. J Neurosci. 2004;24:10040–10046.
- Sempere LF, et al. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biology. 2004;5:R13.
- Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A. Regeneration of a germinal layer in the adult mammalian brain. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:11619–11624.
- Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell. 2003;115:787–798.
- Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature. 2005;436:214–220.
- Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–86.
- Smirnova L, et al. Regulation of miRNA expression during neural cell specification. The European Journal of Neuroscience. 2005;21:1469–1477.
- Panganiban G, Rubenstein JL. Developmental functions of the Distal-less/Dlx homeobox genes. Development. 2002;129:4371–4386.
- Nyfeler Y, et al. Jagged1 signals in the postnatal subventricular zone are required for neural stem cell self-renewal. The EMBO Journal. 2005;24:3504–3515.
- Finzsch M, Stolt CC, Lommes P, Wegner M. Sox9 and Sox10 influence survival and migration of oligodendrocyte precursors in the spinal cord by regulating PDGF receptor {alpha} expression. Development. 2008;135:637–646.
- Stolt CC, et al. The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes & Development. 2003;17:1677–1689.
- Nowak JA, Polak L, Pasolli HA, Fuchs E. Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell. 2008;3:33–43.
- Bastide P, et al. Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. The Journal of Cell Biology. 2007;178:635–648.
- Vidal VP, et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr Biol. 2005;15:1340–1351.
- Krichevsky AM, King KS, Donahue CP, Khrapko K, Kosik KS. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA. 2003;9:1274–1281.
- Bartel DP, Chen CZ. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet. 2004;5:396–400.
- Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell. 2005;121:645–657.
- Singh SK, Kagalwala MN, Parker-Thornburg J, Adams H, Majumder S. REST maintains self-renewal and pluripotency of embryonic stem cells. Nature. 2008;453:223–227.
- Choi PS, et al. Members of the miRNA-200 family regulate olfactory neurogenesis. Neuron. 2008;57:41–55.
- Silber J, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:14.
- Lim DA, et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron. 2000;28:713–726.
Source: PubMed