Letter | Published:

MicroRNA-mediated switching of chromatin-remodelling complexes in neural development

Nature volume 460, pages 642646 (30 July 2009) | Download Citation

  • An Erratum to this article was published on 10 September 2009

Abstract

One of the most distinctive steps in the development of the vertebrate nervous system occurs at mitotic exit when cells lose multipotency and begin to develop stable connections that will persist for a lifetime1,2. This transition is accompanied by a switch in ATP-dependent chromatin-remodelling mechanisms that appears to coincide with the final mitotic division of neurons. This switch involves the exchange of the BAF53a (also known as ACTL6a) and BAF45a (PHF10) subunits within Swi/Snf-like neural-progenitor-specific BAF (npBAF) complexes for the homologous BAF53b (ACTL6b) and BAF45b (DPF1) subunits within neuron-specific BAF (nBAF) complexes in post-mitotic neurons. The subunits of the npBAF complex are essential for neural-progenitor proliferation, and mice with reduced dosage for the genes encoding its subunits have defects in neural-tube closure similar to those in human spina bifida3, one of the most serious congenital birth defects. In contrast, BAF53b and the nBAF complex are essential for an evolutionarily conserved program of post-mitotic neural development and dendritic morphogenesis4,5. Here we show that this essential transition is mediated by repression of BAF53a by miR-9* and miR-124. We find that BAF53a repression is mediated by sequences in the 3′ untranslated region corresponding to the recognition sites for miR-9* and miR-124, which are selectively expressed in post-mitotic neurons. Mutation of these sites led to persistent expression of BAF53a and defective activity-dependent dendritic outgrowth in neurons. In addition, overexpression of miR-9* and miR-124 in neural progenitors caused reduced proliferation. Previous studies have indicated that miR-9* and miR-124 are repressed by the repressor-element-1-silencing transcription factor (REST, also known as NRSF)6. Indeed, expression of REST in post-mitotic neurons led to derepression of BAF53a, indicating that REST-mediated repression of microRNAs directs the essential switch of chromatin regulatory complexes.

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References

  1. 1.

    , , & Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nature Neurosci. 7, 136–144 (2004)

  2. 2.

    The development of neural stem cells. Nature 414, 112–117 (2001)

  3. 3.

    et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201–215 (2007)

  4. 4.

    et al. Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56, 94–108 (2007)

  5. 5.

    , , & Genome-wide analyses identify transcription factors required for proper morphogenesis of Drosophila sensory neuron dendrites. Genes Dev. 20, 820–835 (2006)

  6. 6.

    , , & Reciprocal actions of REST and a microRNA promote neuronal identity. Proc. Natl Acad. Sci. USA 103, 2422–2427 (2006)

  7. 7.

    , & The yeast SNF2/SWI2 protein has DNA-stimulated ATPase activity required for transcriptional activation. Genes Dev. 7, 583–591 (1993)

  8. 8.

    & Characterization of the yeast SWI1, SWI2, and SWI3 genes, which encode a global activator of transcription. Cell 68, 573–583 (1992)

  9. 9.

    , , , & BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature 366, 170–174 (1993)

  10. 10.

    , , & Selectivity of chromatin-remodelling cofactors for ligand-activated transcription. Nature 414, 924–928 (2001)

  11. 11.

    et al. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 10, 2117–2130 (1996)

  12. 12.

    et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005)

  13. 13.

    et al. A pattern-based method for the identification of microRNA binding sites and their corresponding heteroduplexes. Cell 126, 1203–1217 (2006)

  14. 14.

    & Origins and mechanisms of miRNAs and siRNAs. Cell 136, 642–655 (2009)

  15. 15.

    , , & Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 24, 857–864 (2006)

  16. 16.

    et al. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002)

  17. 17.

    & Molecular architecture of a miRNA-regulated 3′ UTR. RNA 14, 1297–1317 (2008)

  18. 18.

    , & Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Rev. Genet. 9, 102–114 (2008)

  19. 19.

    , & A functional study of miR-124 in the developing neural tube. Genes Dev. 21, 531–536 (2007)

  20. 20.

    , , & The microRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol. Cell 27, 435–448 (2007)

  21. 21.

    , , , & The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev. 21, 744–749 (2007)

  22. 22.

    & Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nature Rev. Genet. 9, 831–842 (2008)

  23. 23.

    et al. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747–1752 (2002)

  24. 24.

    , , , & REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005)

  25. 25.

    , & NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nature Genet. 20, 136–142 (1998)

  26. 26.

    et al. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80, 949–957 (1995)

  27. 27.

    & The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360–1363 (1995)

  28. 28.

    , , , & A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116, 779–793 (2004)

  29. 29.

    et al. A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol. Cell 6, 1287–1295 (2000)

  30. 30.

    et al. Srg3, a mouse homolog of yeast SWI3, is essential for early embryogenesis and involved in brain development. Mol. Cell. Biol. 21, 7787–7795 (2001)

  31. 31.

    , , , & Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res. 33, e36 (2005)

  32. 32.

    et al. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401, 703–708 (1999)

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Acknowledgements

We thank J. I. Wu and J. Lessard for suggestions. We thank N. Copeland and N. Jenkins for providing us with the reagents for recombineering techniques. A.S.Y. is a fellow of Helen Hay Whitney Foundation. B.T.S. is supported by the Developmental and Neonatal Biology Training Program 2 T32 HD007249 from the US National Institutes of Health (NIH). This work was supported by grants from the Howard Hughes Medical Institute and the NIH, HD55391, AI060037 and NS046789, to G.R.C.

Author Contributions A.S.Y. and G.R.C. generated the hypotheses, designed experiments and wrote the manuscript. A.S.Y. performed experiments and generated Figs 1, 2, 3 and 4 and supplementary data. B.T.S. and A.S.Y. performed experiments for Figs 3 and 4. L.C. performed the pronuclear injections used in generating transgenic mouse embryos.

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Affiliations

  1. Howard Hughes Medical Institute,

    • Andrew S. Yoo
    • , Brett T. Staahl
    • , Lei Chen
    •  & Gerald R. Crabtree
  2. Department of Developmental Biology,

    • Andrew S. Yoo
    • , Brett T. Staahl
    • , Lei Chen
    •  & Gerald R. Crabtree
  3. Department of Pathology, Stanford University, Stanford, California 94305, USA

    • Andrew S. Yoo
    • , Lei Chen
    •  & Gerald R. Crabtree

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Correspondence to Gerald R. Crabtree.

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    Supplementary Information

    This file contains Supplementary Figures 1-6 with Legends and Supplementary References.

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https://doi.org/10.1038/nature08139

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