Dicer is required for neural stem cell multipotency and lineage progression during cerebral cortex development

Neural Development

Frederick J Livesey²  Zoltán Molnár¹  Navneet A Vasistha¹  Therese Andersson²  Nathalie Saurat² 

[1] Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK;Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR

关键词: Multipotency;    microRNA;    Dicer;    Stem cells;    Cerebral cortex;   

Others  :  804460
DOI  :  10.1186/1749-8104-8-14

 received in 2012-11-06, accepted in 2013-05-22,  发布年份 2013

【 摘 要 】

Background

During cerebral cortex development, multipotent neural progenitor cells generate a variety of neuronal subtypes in a fixed temporal order. How a single neural progenitor cell generates the diversity of cortical projection neurons in a temporal sequence is not well understood. Based on their function in developmental timing in other systems, Dicer and microRNAs are potential candidate regulators of cellular pathways that control lineage progression in neural systems.

Results

Cortex-specific deletion of Dicer results in a marked reduction in the cellular complexity of the cortex, due to a pronounced narrowing in the range of neuronal types generated by Dicer-null cortical stem and progenitor cells. Instead of generating different classes of lamina-specific neurons in order over the 6-day period of neurogenesis, Dicer null cortical stem and progenitor cells continually produce one class of deep layer projection neuron. However, gliogenesis in the Dicer-null cerebral cortex was not delayed, despite the loss of multipotency and the failure of neuronal lineage progression.

Conclusions

We conclude that Dicer is required for regulating cortical stem cell multipotency with respect to neuronal diversity, without affecting the larger scale switch from neurogenesis to gliogenesis. The differences in phenotypes reported from different timings of Dicer deletion indicate that the molecular pathways regulating developmental transitions are notably dosage sensitive.

【 授权许可】

   
2013 Saurat et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Mountcastle VB: The Cerebral Cortex. Cambridge, MA: Harvard University Press; 1998.
• [2]McConnell SK: The generation of neuronal diversity in the central nervous system. Annu Rev Neurosci 1991, 14:269-300.
• [3]Frantz GD, McConnell SK: Restriction of late cerebral cortical progenitors to an upper-layer fate. Neuron 1996, 17:55-61.
• [4]Qian X, Shen Q, Goderie SK, He W, Capela A, Davis AA, Temple S: Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 2000, 28:69-80.
• [5]Livesey FJ, Cepko CL: Vertebrate neural cell-fate determination: lessons from the retina. Nat Rev Neurosci 2001, 2:109-118.
• [6]Shen Q, Wang Y, Dimos JT, Fasano CA, Phoenix TN, Lemischka IR, Ivanova NB, Stifani S, Morrisey EE, Temple S: The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nat Neurosci 2006, 9:743-751.
• [7]Sokol NS: Small temporal RNAs in animal development. Curr Opin Genet Dev 2012, 22:368-373.
• [8]Ambros V: Control of developmental timing in Caenorhabditis elegans. Curr Opin Genet Dev 2000, 10:428-433.
• [9]Kawahara H, Imai T, Okano H: MicroRNAs in neural stem cells and neurogenesis. Front Neurosci 2012, 6:30.
• [10]Bonev B, Pisco A, Papalopulu N: MicroRNA-9 reveals regional diversity of neural progenitors along the anterior-posterior axis. Dev Cell 2011, 20:19-32.
• [11]Cao X, Pfaff SL, Gage FH: A functional study of miR-124 in the developing neural tube. Genes Dev 2007, 21:531-536.
• [12]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.
• [13]Andersson T, Rahman S, Sansom SN, Alsio JM, Kaneda M, Smith J, O’Carroll D, Tarakhovsky A, Livesey FJ: Reversible block of mouse neural stem cell differentiation in the absence of dicer and microRNAs. PLoS One 2010, 5:e13453.
• [14]Kawase-Koga Y, Low R, Otaegi G, Pollock A, Deng H, Eisenhaber F, Maurer-Stroh S, Sun T: RNAase-III enzyme Dicer maintains signaling pathways for differentiation and survival in mouse cortical neural stem cells. J Cell Sci 2010, 123:586-594.
• [15]De Pietri TD, Pulvers JN, Haffner C, Murchison EP, Hannon GJ, Huttner WB: miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex. Development 2008, 135:3911-3921.
• [16]Kawase-Koga Y, Otaegi G, Sun T: Different timings of Dicer deletion affect neurogenesis and gliogenesis in the developing mouse central nervous system. Dev Dyn 2009, 238:2800-2812.
• [17]Nowakowski TJ, Mysiak KS, Pratt T, Price DJ: Functional Dicer is necessary for appropriate specification of radial glia during early development of mouse telencephalon. PLoS One 2011, 6:e23013.
• [18]Georgi SA, Reh TA: Dicer is required for the transition from early to late progenitor state in the developing mouse retina. J Neurosci 2010, 30:4048-4061.
• [19]McLoughlin HS, Fineberg SK, Ghosh LL, Tecedor L, Davidson BL: Dicer is required for proliferation, viability, migration and differentiation in corticoneurogenesis. Neuroscience 2012, 223:285-295.
• [20]Zheng K, Li H, Zhu Y, Zhu Q, Qiu M: MicroRNAs are essential for the developmental switch from neurogenesis to gliogenesis in the developing spinal cord. J Neurosci 2010, 30:8245-8250.
• [21]Schaefer A, O’Carroll D, Tan CL, Hillman D, Sugimori M, Llinas R, Greengard P: Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med 2007, 204:1553-1558.
• [22]Damiani D, Alexander JJ, O’Rourke JR, McManus M, Jadhav AP, Cepko CL, Hauswirth WW, Harfe BD, Strettoi E: Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina. J Neurosci 2008, 28:4878-4887.
• [23]Davis TH, Cuellar TL, Koch SM, Barker AJ, Harfe BD, McManus MT, Ullian EM: Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci 2008, 28:4322-4330.
• [24]Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, Jones KR: Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci 2002, 22:6309-6314.
• [25]Yi R, O’Carroll D, Pasolli HA, Zhang Z, Dietrich FS, Tarakhovsky A, Fuchs E: Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat Genet 2006, 38:356-362.
• [26]Sansom SN, Hebert JM, Thammongkol U, Smith J, Nisbet G, Surani MA, McConnell SK, Livesey FJ: Genomic characterisation of a Fgf-regulated gradient-based neocortical protomap. Development 2005, 132:3947-3961.
• [27]Pereira JD, Sansom SN, Smith J, Dobenecker MW, Tarakhovsky A, Livesey FJ: Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci U S A 2010, 107:15957-15962.
• [28]Schmittgen TD, Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008, 3:1101-1108.
• [29]Molnar Z, Blakey D, Bystron I, Carney RM: Tract-tracing in developing systems and in post-mortem human material. In Neuroanatomical Tract-tracing 3: Molecules, Neurons, and Systems. Edited by Zaborszky L, Wouterlood FG, Lanciego JL. New York, NY: Springer/Kluwer/Plenum; 2006.
• [30]Hevner RF, Daza RA, Rubenstein JL, Stunnenberg H, Olavarria JF, Englund C: Beyond laminar fate: toward a molecular classification of cortical projection/pyramidal neurons. Dev Neurosci 2003, 25:139-151.
• [31]Nishino J, Kim I, Chada K, Morrison SJ: Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell 2008, 135:227-239.
• [32]Lee YS, Dutta A: The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 2007, 21:1025-1030.
• [33]Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, Li Y, Ali S, Sethi S, Hassan O, Hwang C, Gupta N, Chitale D, Sakr WA, Menon M, Sarkar FH: Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS One 2012, 7:e33729.
• [34]Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA: A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 2008, 28:264-278.
• [35]Sansom SN, Griffiths DS, Faedo A, Kleinjan DJ, Ruan Y, Smith J, van Heyningen V, Rubenstein JL, Livesey FJ: The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genet 2009, 5:e1000511.
• [36]Chen B, Wang SS, Hattox AM, Rayburn H, Nelson SB, McConnell SK: The Fezf2-Ctip2 genetic pathway regulates the fate choice of subcortical projection neurons in the developing cerebral cortex. Proc Natl Acad Sci U S A 2008, 105:11382-11387.