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HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the β-catenin–TCF interaction

Abstract

Oligodendrocyte development is regulated by the interaction of repressors and activators in a complex transcriptional network. We found that two histone-modifying enzymes, HDAC1 and HDAC2, were required for oligodendrocyte formation. Genetic deletion of both Hdac1 and Hdac2 in oligodendrocyte lineage cells resulted in stabilization and nuclear translocation of β-catenin, which negatively regulates oligodendrocyte development by repressing Olig2 expression. We further identified the oligodendrocyte-restricted transcription factor TCF7L2/TCF4 as a bipartite co-effector of β-catenin for regulating oligodendrocyte differentiation. Targeted disruption of Tcf7l2 in mice led to severe defects in oligodendrocyte maturation, whereas expression of its dominant-repressive form promoted precocious oligodendrocyte specification in developing chick neural tube. Transcriptional co-repressors HDAC1 and HDAC2 compete with β-catenin for TCF7L2 interaction to regulate downstream genes involved in oligodendrocyte differentiation. Thus, crosstalk between HDAC1/2 and the canonical Wnt signaling pathway mediated by TCF7L2 serves as a regulatory mechanism for oligodendrocyte differentiation.

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Figure 1: Hdac1 and Hdac2 are required for oligodendrocyte development in the spinal cord.
Figure 2: Hdac1 and Hdac2 are essential for oligodendrocyte differentiation in vitro and are not required for motor neurons and astrocyte development.
Figure 3: Activation of Wnt signaling by stabilizing β-catenin in Hdac1 and Hdac2 mutant progenitors.
Figure 4: Activation of canonical Wnt signaling in oligodendrocyte lineage cells inhibits oligodendrocyte differentiation.
Figure 5: Identification of the Wnt/β-catenin effector TCF7L2 as being an oligodendrocyte-specific transcription factor.
Figure 6: A dominant-repressive form of Tcf7l2 promotes ectopic and precocious oligodendrocyte specification.
Figure 7: Competition between β-catenin and HDAC1/2 proteins for TCF7L2 interaction regulates the expression of Wnt target genes.

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References

  1. Hsieh, J. & Gage, F.H. Chromatin remodeling in neural development and plasticity. Curr. Opin. Cell Biol. 17, 664–671 (2005).

    Article  CAS  Google Scholar 

  2. Gregoretti, I.V., Lee, Y.M. & Goodson, H.V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338, 17–31 (2004).

    Article  CAS  Google Scholar 

  3. Marin-Husstege, M., Muggironi, M., Liu, A. & Casaccia-Bonnefil, P. Histone deacetylase activity is necessary for oligodendrocyte lineage progression. J. Neurosci. 22, 10333–10345 (2002).

    Article  CAS  Google Scholar 

  4. Shen, S., Li, J. & Casaccia-Bonnefil, P. Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. J. Cell Biol. 169, 577–589 (2005).

    Article  CAS  Google Scholar 

  5. Cunliffe, V.T. & Casaccia-Bonnefil, P. Histone deacetylase 1 is essential for oligodendrocyte specification in the zebrafish CNS. Mech. Dev. 123, 24–30 (2006).

    Article  CAS  Google Scholar 

  6. Lu, Q.R. et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109, 75–86 (2002).

    Article  CAS  Google Scholar 

  7. Zhou, Q. & Anderson, D.J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002).

    Article  CAS  Google Scholar 

  8. Takebayashi, H., Nabeshima, Y., Yoshida, S., Chisaka, O. & Ikenaka, K. The basic helix-loop-helix factor olig2 is essential for the development of motoneuron and oligodendrocyte lineages. Curr. Biol. 12, 1157–1163 (2002).

    Article  CAS  Google Scholar 

  9. Clevers, H. Wnt/beta-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    Article  CAS  Google Scholar 

  10. Grigoryan, T., Wend, P., Klaus, A. & Birchmeier, W. Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev. 22, 2308–2341 (2008).

    Article  CAS  Google Scholar 

  11. Hurlstone, A. & Clevers, H. T-cell factors: turn-ons and turn-offs. EMBO J. 21, 2303–2311 (2002).

    Article  CAS  Google Scholar 

  12. Billin, A.N., Thirlwell, H. & Ayer, D.E. Beta-catenin–histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator. Mol. Cell. Biol. 20, 6882–6890 (2000).

    Article  CAS  Google Scholar 

  13. Shimizu, T. et al. Wnt signaling controls the timing of oligodendrocyte development in the spinal cord. Dev. Biol. 282, 397–410 (2005).

    Article  CAS  Google Scholar 

  14. Yamaguchi, M. et al. Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways. Development 132, 3027–3043 (2005).

    Article  CAS  Google Scholar 

  15. Montgomery, R.L. et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 21, 1790–1802 (2007).

    Article  CAS  Google Scholar 

  16. Xin, M. et al. Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice. J. Neurosci. 25, 1354–1365 (2005).

    Article  CAS  Google Scholar 

  17. Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    Article  CAS  Google Scholar 

  18. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  Google Scholar 

  19. Nave, K.A. Neurological mouse mutants and the genes of myelin. J. Neurosci. Res. 38, 607–612 (1994).

    Article  CAS  Google Scholar 

  20. Nishiyama, A., Lin, X.H., Giese, N., Heldin, C.H. & Stallcup, W.B. Co-localization of NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells in the developing rat brain. J. Neurosci. Res. 43, 299–314 (1996).

    Article  CAS  Google Scholar 

  21. Arber, S. et al. Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron 23, 659–674 (1999).

    Article  CAS  Google Scholar 

  22. Hsieh, J. et al. IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. J. Cell Biol. 164, 111–122 (2004).

    Article  CAS  Google Scholar 

  23. Korinek, V. et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science 275, 1784–1787 (1997).

    Article  CAS  Google Scholar 

  24. Maretto, S. et al. Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. Proc. Natl. Acad. Sci. USA 100, 3299–3304 (2003).

    Article  CAS  Google Scholar 

  25. Chen, Y. et al. Isolation and culture of rat and mouse oligodendrocyte precursor cells. Nat. Protoc. 2, 1044–1051 (2007).

    Article  CAS  Google Scholar 

  26. van Noort, M., Meeldijk, J., van der Zee, R., Destree, O. & Clevers, H. Wnt signaling controls the phosphorylation status of beta-catenin. J. Biol. Chem. 277, 17901–17905 (2002).

    Article  CAS  Google Scholar 

  27. Barres, B.A., Lazar, M.A. & Raff, M.C. A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development 120, 1097–1108 (1994).

    CAS  Google Scholar 

  28. Stankoff, B. et al. Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules. J. Neurosci. 22, 9221–9227 (2002).

    Article  CAS  Google Scholar 

  29. Harada, N. et al. Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J. 18, 5931–5942 (1999).

    Article  CAS  Google Scholar 

  30. Lappe-Siefke, C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat. Genet. 33, 366–374 (2003).

    Article  CAS  Google Scholar 

  31. Munemitsu, S., Albert, I., Rubinfeld, B. & Polakis, P. Deletion of an amino-terminal sequence beta-catenin in vivo and promotes hyperphosporylation of the adenomatous polyposis coli tumor suppressor protein. Mol. Cell. Biol. 16, 4088–4094 (1996).

    Article  CAS  Google Scholar 

  32. Wang, S.Z. et al. An oligodendrocyte-specific zinc-finger transcription regulator cooperates with Olig2 to promote oligodendrocyte differentiation. Development 133, 3389–3398 (2006).

    Article  CAS  Google Scholar 

  33. Ono, K., Bansal, R., Payne, J., Rutishauser, U. & Miller, R.H. Early development and dispersal of oligodendrocyte precursors in the embryonic chick spinal cord. Development 121, 1743–1754 (1995).

    CAS  PubMed  Google Scholar 

  34. Kardon, G., Harfe, B.D. & Tabin, C.J.A. Tcf4-positive mesodermal population provides a prepattern for vertebrate limb muscle patterning. Dev. Cell 5, 937–944 (2003).

    Article  CAS  Google Scholar 

  35. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 19, 379–383 (1998).

    Article  CAS  Google Scholar 

  36. Wang, S., Sdrulla, A., Johnson, J.E., Yokota, Y. & Barres, B.A. A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development. Neuron 29, 603–614 (2001).

    Article  CAS  Google Scholar 

  37. Kondo, T. & Raff, M. The Id4 HLH protein and the timing of oligodendrocyte differentiation. EMBO J. 19, 1998–2007 (2000).

    Article  CAS  Google Scholar 

  38. Wang, S. et al. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21, 63–75 (1998).

    Article  Google Scholar 

  39. Memezawa, A. et al. Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes. Oncogene 26, 5038–5045 (2007).

    Article  CAS  Google Scholar 

  40. Rockman, S.P. et al. Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma. J. Biol. Chem. 276, 45113–45119 (2001).

    Article  CAS  Google Scholar 

  41. Yu, L. et al. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat. Genet. 37, 265–274 (2005).

    Article  CAS  Google Scholar 

  42. Miskimins, R., Srinivasan, R., Marin-Husstege, M., Miskimins, W.K. & Casaccia-Bonnefil, P. p27(Kip1) enhances myelin basic protein gene promoter activity. J. Neurosci. Res. 67, 100–105 (2002).

    Article  CAS  Google Scholar 

  43. Shen, S. et al. Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci. 11, 1024–1034 (2008).

    Article  CAS  Google Scholar 

  44. Hasty, P. et al. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature 364, 501–506 (1993).

    Article  CAS  Google Scholar 

  45. Brantjes, H., Roose, J., van De Wetering, M. & Clevers, H. All Tcf HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Res. 29, 1410–1419 (2001).

    Article  CAS  Google Scholar 

  46. Bolden, J.E., Peart, M.J. & Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769–784 (2006).

    Article  CAS  Google Scholar 

  47. Minucci, S. & Pelicci, P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 6, 38–51 (2006).

    Article  CAS  Google Scholar 

  48. Kuwabara, T., Hsieh, J., Nakashima, K., Taira, K. & Gage, F.H. A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116, 779–793 (2004).

    Article  CAS  Google Scholar 

  49. Gabay, L., Lowell, S., Rubin, L.L. & Anderson, D.J. Deregulation of dorsoventral patterning by FGF confers trilineage differentiation capacity on CNS stem cells in vitro. Neuron 40, 485–499 (2003).

    Article  CAS  Google Scholar 

  50. Megason, S.G. & McMahon, A.P. A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. Development 129, 2087–2098 (2002).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank J. Johnson and B. Cregg for a critical reading of the manuscript and D. Rowitch for communicating their unpublished results. We thank W. Walker, A. Iavarone, Y. Yokota, K. Kim, R. Miskimins and J. Suh for Id2 and Id4, Mbp promoter reporters, and β-catenin and TCF expression vectors, and X. Xu for technical assistance. This study was funded by grants from the US National Multiple Sclerosis Society (RG3978 and PP0144) and the US National Institutes of Health (NS050389 to Q.R.L.). Q.R.L. is a Harry Weaver Neuroscience Scholar and a Basil O'Connor Scholar.

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Contributions

Q.R.L. designed the study, analyzed the data and coordinated the project. F.Y., Y.C., T.N.H., X.-H.Z. and T.H. performed the morphological analysis and biochemical assays. H.B. provided resources. M.M.T. provided the Ctnnb1ex3 mice. J.H.E. and H.C. provided TCF7l2 mutant mice. J.H. provided HCN cell culture. R.L.M., R.B.-D. and E.N.O. provided Hdac1loxP/loxP and Hdac2loxP/loxP mice and contributed conceptually to the project. The manuscript was written by Q.R.L., edited by R.B.D. and E.N.O., and commented on by all authors.

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Correspondence to Q Richard Lu.

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Ye, F., Chen, Y., Hoang, T. et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the β-catenin–TCF interaction. Nat Neurosci 12, 829–838 (2009). https://doi.org/10.1038/nn.2333

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