The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex

Neural Development

Brian Hendrich²  Frederick J Livesey²  Donna Leaford³  Andrew Dimond²  Patrick D Lombard³  João Pereira²  Erin Knock¹ 

[1] Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, 6KD-404, 60 Leonard Avenue, Toronto, ON, Canada;Department of Biochemistry, University of Cambridge, Cambridge, UK;Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK

关键词: Gene expression;    Neural differentiation;    Neural progenitors;   

Others  :  1210965
DOI  :  10.1186/s13064-015-0040-z

 received in 2014-12-19, accepted in 2015-04-17,  发布年份 2015

【 摘 要 】

Background

Chromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis. The methyl binding domain 3/nucleosome remodelling and deacetylation (MBD3/NuRD) co-repressor complex facilitates lineage commitment of pluripotent cells in early mouse embryos and is important for stem cell homeostasis in blood and skin, but its function in neurogenesis had not been described. Here, we show for the first time that MBD3/NuRD function is essential for normal neurogenesis in mice.

Results

Deletion of MBD3, a structural component of the NuRD complex, in the developing mouse central nervous system resulted in reduced cortical thickness, defects in the proper specification of cortical projection neuron subtypes and neonatal lethality. These phenotypes are due to alterations in PAX6+ apical progenitor cell outputs, as well as aberrant terminal neuronal differentiation programmes of cortical plate neurons. Normal numbers of PAX6+ apical neural progenitor cells were generated in the MBD3/NuRD-mutant cortex; however, the PAX6+ apical progenitor cells generate EOMES+ basal progenitor cells in reduced numbers. Cortical progenitor cells lacking MBD3/NuRD activity generate neurons that express both deep- and upper-layer markers. Using laser capture microdissection, gene expression profiling and chromatin immunoprecipitation, we provide evidence that MBD3/NuRD functions to control gene expression patterns during neural development.

Conclusions

Our data suggest that although MBD3/NuRD is not required for neural stem cell lineage commitment, it is required to repress inappropriate transcription in both progenitor cells and neurons to facilitate appropriate cell lineage choice and differentiation programmes.

【 授权许可】

   
2015 Knock et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Rakic P: The radial edifice of cortical architecture: from neuronal silhouettes to genetic engineering. Brain Res Rev 2007, 55:204-19.
• [2]Hirabayashi Y, Gotoh Y: Epigenetic control of neural precursor cell fate during development. Nat Rev Neurosci 2010, 11:377-88.
• [3]Pontious A, Kowalczyk T, Englund C, Hevner RF: Role of intermediate progenitor cells in cerebral cortex development. Dev Neurosci 2008, 30:24-32.
• [4]Ahringer J: NuRD and SIN3 histone deacetylase complexes in development. Trends Genet 2000, 16:351-6.
• [5]McDonel P, Costello I, Hendrich B: Keeping things quiet: roles of NuRD and Sin3 co-repressor complexes during mammalian development. Int J Biochem Cell B 2009, 41:108-16.
• [6]Le Guezennec X, Vermeulen M, Brinkman AB, Hoeijmakers WA, Cohen A, Lasonder E, et al.: MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol Cell Biol 2006, 26:843-51.
• [7]Hendrich B, Guy J, Ramsahoye B, Wilson VA, Bird A: Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev 2001, 15:710-23.
• [8]Kaji K, Nichols J, Hendrich B: Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development 2007, 134:1123-32.
• [9]Smits AH, Jansen PW, Poser I, Hyman AA, Vermeulen M: Stoichiometry of chromatin-associated protein complexes revealed by label-free quantitative mass spectrometry-based proteomics. Nucleic Acids Res 2013., 41Article ID e28
• [10]Kloet SL, Baymaz HI, Makowski M, Groenewold V, Jansen PW, Berendsen M, et al. Towards elucidating the stability, dynamics and architecture of the nucleosome remodeling and deacetylase complex by using quantitative interaction proteomics. FEBS J. 2014; doi:10.1111/febs.12972.
• [11]Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D: Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev 1999, 13:1924-35.
• [12]Kaji K, Caballero IM, MacLeod R, Nichols J, Wilson VA, Hendrich B: The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol 2006, 8:285-92.
• [13]Hendrich B, Tweedie S: The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet 2003, 19:269-77.
• [14]Kashiwagi M, Morgan BA, Georgopoulos K: The chromatin remodeler Mi-2beta is required for establishment of the basal epidermis and normal differentiation of its progeny. Development 2007, 134:1571-82.
• [15]Williams CJ, Naito T, Arco PG, Seavitt JR, Cashman SM, De Souza B, et al.: The chromatin remodeler Mi-2beta is required for CD4 expression and T cell development. Immunity 2004, 20:719-33.
• [16]Yoshida T, Hazan I, Zhang J, Ng SY, Naito T, Snippert HJ, et al.: The role of the chromatin remodeler Mi-2{beta} in hematopoietic stem cell self-renewal and multilineage differentiation. Genes Dev 2008, 22:1174-89.
• [17]Reynolds N, Latos P, Hynes-Allen A, Loos R, Leaford D, O’Shaughnessy A, et al.: NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment. Cell Stem Cell 2012, 10:583-94.
• [18]Jung BP, Zhang G, Nitsch R, Trogadis J, Nag S, Eubanks JH: Differential expression of methyl CpG-binding domain containing factor MBD3 in the developing and adult rat brain. J Neurobiol 2003, 55:220-32.
• [19]Britanova O, De Juan RC, Cheung A, Kwan KY, Schwark M, Gyorgy A, et al.: Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron 2008, 57:378-92.
• [20]Gyorgy AB, Szemes M, de Juan RC, Tarabykin V, Agoston DV: SATB2 interacts with chromatin-remodeling molecules in differentiating cortical neurons. Eur J Neurosci 2008, 27:865-73.
• [21]Yamada T, Yang Y, Hemberg M, Yoshida T, Cho HY, Murphy JP, et al.: Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain. Neuron 2014, 83:122-34.
• [22]Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, et al.: Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet 1999, 23:99-103.
• [23]Zimmerman L, Parr B, Lendahl U, Cunningham M, McKay R, Gavin B, et al.: Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors. Neuron 1994, 12:11-24.
• [24]Duan D, Fu Y, Paxinos G, Watson C: Spatiotemporal expression patterns of Pax6 in the brain of embryonic, newborn, and adult mice. Brain Struct Funct 2013, 218:353-72.
• [25]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, 107:15957-62.
• [26]Sims JK, Wade PA: Mi-2/NuRD complex function is required for normal S phase progression and assembly of pericentric heterochromatin. Mol Biol Cell 2011, 22:3094-102.
• [27]Polo SE, Kaidi A, Baskcomb L, Galanty Y, Jackson SP: Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. EMBO J 2010, 29:3130-9.
• [28]Takahashi T, Nowakowski RS, Caviness VS Jr: The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall. J Neurosci 1995, 15:6046-57.
• [29]Cai L, Morrow EM, Cepko CL: Misexpression of basic helix-loop-helix genes in the murine cerebral cortex affects cell fate choices and neuronal survival. Development 2000, 127:3021-30.
• [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, 25:139-51.
• [31]Reynolds N, Salmon-Divon M, Dvinge H, Hynes-Allen A, Balasooriya G, Leaford D, et al.: NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repression. EMBO J 2012, 31:593-605.
• [32]Ernst J, Bar-Joseph Z: STEM: a tool for the analysis of short time series gene expression data. BMC Bioinformatics 2006, 7:191. BioMed Central Full Text
• [33]Reynolds N, O’Shaughnessy A, Hendrich B: Transcriptional repressors: multifaceted regulators of gene expression. Development 2013, 140:505-12.
• [34]Cameron RS, Rakic P: Glial cell lineage in the cerebral cortex: a review and synthesis. Glia 1991, 4:124-37.
• [35]Kim WY: NeuroD1 is an upstream regulator of NSCL1. Biochem Biophys Res Commun 2012, 419:27-31.
• [36]Bertrand N, Castro DS, Guillemot F: Proneural genes and the specification of neural cell types. Nat Rev Neurosci 2002, 3:517-30.
• [37]Copray S, Huynh JL, Sher F, Casaccia-Bonnefil P, Boddeke E: Epigenetic mechanisms facilitating oligodendrocyte development, maturation, and aging. Glia 2009, 57:1579-87.
• [38]Menet V: Gimenez y Ribotta M, Chauvet N, Drian MJ, Lannoy J, Colucci-Guyon E, et al. Inactivation of the glial fibrillary acidic protein gene, but not that of vimentin, improves neuronal survival and neurite growth by modifying adhesion molecule expression. J Neurosci 2001, 21:6147-58.
• [39]Ohsawa R, Ohtsuka T, Kageyama R: Mash1 and Math3 are required for development of branchiomotor neurons and maintenance of neural progenitors. J Neurosci 2005, 25:5857-65.
• [40]Yamada M, Sato N, Ikeda S, Arai T, Sawabe M, Mori S, et al.: Association of the chromodomain helicase DNA-binding protein 4 (CHD4) missense variation p.D140E with cancer: potential interaction with smoking. Genes Chromosomes Canc 2015, 54:122-8.
• [41]Latos PA, Helliwell C, Mosaku O, Dudzinska DA, Stubbs B, Berdasco M, et al.: NuRD-dependent DNA methylation prevents ES cells from accessing a trophectoderm fate. Biology Open 2012, 1:341-52.
• [42]Signolet J, Hendrich B: The function of chromatin modifiers in lineage commitment and cell fate specification. FEBS J 2014, 282(9):1692-702.
• [43]Ogas J, Kaufmann S, Henderson J, Somerville C: PICKLE is a CHD3 chromatin-remodeling factor that regulates the transition from embryonic to vegetative development in Arabidopsis. Proc Natl Acad Sci U S A 1999, 96:13839-44.
• [44]Unhavaithaya Y, Shin TH, Miliaras N, Lee J, Oyama T, Mello CC: MEP-1 and a homolog of the NURD complex component Mi-2 act together to maintain germline-soma distinctions in C. elegans. Cell 2002, 111:991-1002.
• [45]Aguilera C, Nakagawa K, Sancho R, Chakraborty A, Hendrich B, Behrens A: c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature 2011, 469:231-5.
• [46]Du P, Kibbe WA, Lin SM: Lumi: a pipeline for processing Illumina microarray. Bioinformatics 2008, 24:1547-8.
• [47]Smyth GK: Limma: linear models for microarray data. In Bioinformatics and computational biology solutions using R and Bioconductor. Edited by Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W. Springer, New York; 2005:397-420.