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Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development

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Abstract

Abnormal expression and dysfunction of methyl-CpG binding protein 2 (MeCP2) cause Rett syndrome (RTT). The diverse phosphorylation modifications modulate MeCP2 function in neural cells. Using western blot and immunohistochemistry, we examined the expression patterns of MeCP2 and three phospho-MeCP2s (pMeCP2s) in the developing rat brain. The expression of MeCP2 and phospho-S80 (pS80) MeCP2 increased while pS421 MeCP2 and pS292 MeCP2 decreased with brain maturation. In contrast to the nuclear localization of MeCP2 and pS80 MeCP2, pS421 MeCP2 and pS292 MeCP2 were mainly expressed in the cytoplasmic compartment. Apart from their distribution in neurons, they were also detected at a low level in astrocytes. Postnatally-initiated MeCP2 deficiency affected cerebellar neural cell development, as determined by the abnormal expression of GFAP, DCX, Tuj1, MAP-2, and calbindin-D28k. Together, these results demonstrate that MeCP2 and diverse pMeCP2s have distinct features of spatio-temporal expression in the rat brain, and that the precise levels of MeCP2 in the postnatal period are vital to cerebellar neural cell development.

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References

  1. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 2008, 320: 1224–1229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Damen D, Heumann R. MeCP2 phosphorylation in the brain: from transcription to behavior. Biol Chem 2013, 394: 1595–1605.

    Article  CAS  PubMed  Google Scholar 

  3. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 2006, 52: 255–269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tao J, Hu K, Chang Q, Wu H, Sherman NE, Martinowich K, et al. Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function. Proc Natl Acad Sci U S A 2009, 106: 4882–4887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Li H, Zhong X, Chau KF, Williams EC, Chang Q. Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory. Nat Neurosci 2011, 14: 1001–1008.

    Article  CAS  PubMed  Google Scholar 

  6. Cohen S, Gabel HW, Hemberg M, Hutchinson AN, Sadacca LA, Ebert DH, et al. Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 2011, 72: 72–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cheng TL, Qiu Z. MeCP2: multifaceted roles in gene regulation and neural development. Neurosci Bull 2014, 30: 601–609.

    Article  CAS  PubMed  Google Scholar 

  8. Liu F, Ni JJ, Huang JJ, Kou ZW, Sun FY. VEGF overexpression enhances the accumulation of phospho-S292 MeCP2 in reactive astrocytes in the adult rat striatum following cerebral ischemia. Brain Res 2015, 1599: 32–43.

    Article  CAS  PubMed  Google Scholar 

  9. Gonzales ML, Adams S, Dunaway KW, LaSalle JM. Phosphorylation of distinct sites in MeCP2 modifies cofactor associations and the dynamics of transcriptional regulation. Mol Cell Biol 2012, 32: 2894–2903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mullaney BC, Johnston MV, Blue ME. Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain. Neuroscience 2004, 123: 939–949.

    Article  CAS  PubMed  Google Scholar 

  11. Ballas N, Lioy DT, Grunseich C, Mandel G. Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci 2009, 12: 311–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Maezawa I, Jin LW. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J Neurosci 2010, 30: 5346–5356.

    Article  CAS  PubMed  Google Scholar 

  13. Miyake K, Nagai K. Phosphorylation of methyl-CpG binding protein 2 (MeCP2) regulates the intracellular localization during neuronal cell differentiation. Neurochem Int 2007, 50: 264–270.

    Article  CAS  PubMed  Google Scholar 

  14. Aber KM, Nori P, MacDonald SM, Bibat G, Jarrar MH, Kaufmann WE. Methyl-CpG-binding protein 2 is localized in the postsynaptic compartment: an immunochemical study of subcellular fractions. Neuroscience 2003, 116: 77–80.

    Article  CAS  PubMed  Google Scholar 

  15. Li X, Liu X, Guo H, Zhao Z, Li YS, Chen G. The significance of the increased expression of phosphorylated MeCP2 in the membranes from patients with proliferative diabetic retinopathy. Sci Rep 2016, 6: 32850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999, 23: 185–188.

    Article  CAS  PubMed  Google Scholar 

  17. Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 1983, 14: 471–479.

    Article  CAS  PubMed  Google Scholar 

  18. Bebbington A, Downs J, Percy A, Pineda M, Zeev BB, Bahi-Buisson N, et al. The phenotype associated with a large deletion on MECP2. Eur J Hum Genet 2012, 20: 921–927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jellinger K, Armstrong D, Zoghbi HY, Percy AK. Neuropathology of Rett syndrome. Acta Neuropathol 1988, 76: 142–158.

    Article  CAS  PubMed  Google Scholar 

  20. Na ES, Monteggia LM. The role of MeCP2 in CNS development and function. Horm Behav 2011, 59: 364–368.

    Article  CAS  PubMed  Google Scholar 

  21. Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 2001, 27: 322–326.

    Article  CAS  PubMed  Google Scholar 

  22. Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet 2004, 13: 2679–2689.

    Article  CAS  PubMed  Google Scholar 

  23. Guy J, Gan J, Selfridge J, Cobb S, Bird A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 2007, 315: 1143–1147.

    Article  CAS  PubMed  Google Scholar 

  24. Nguyen MV, Du F, Felice CA, Shan X, Nigam A, Mandel G, et al. MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. J Neurosci 2012, 32: 10021–10034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cheval H, Guy J, Merusi C, De Sousa D, Selfridge J, Bird A. Postnatal inactivation reveals enhanced requirement for MeCP2 at distinct age windows. Hum Mol Genet 2012, 21: 3806–3814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tfilin M, Sudai E, Merenlender A, Gispan I, Yadid G, Turgeman G. Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol Psychiatry 2009, 15: 1164–1175.

    Article  PubMed  Google Scholar 

  27. Petrov ES, Varlinskaya EI, Smotherman WP. The first suckling episode in the rat: the role of endogenous activity at mu and kappa opioid receptors. Dev Psychobiol 2000, 37: 129–143.

    Article  CAS  PubMed  Google Scholar 

  28. Song C, Feodorova Y, Guy J, Peichl L, Jost KL, Kimura H, et al. DNA methylation reader MECP2: cell type- and differentiation stage-specific protein distribution. Epigenetics Chromatin 2014, 7: 17.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet 2002, 11: 115–124.

    Article  CAS  PubMed  Google Scholar 

  30. Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, MacLeod PJ, et al. A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet 2004, 36: 339–341.

    Article  CAS  PubMed  Google Scholar 

  31. Jung BP, Jugloff DG, Zhang G, Logan R, Brown S, Eubanks JH. The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells. J Neurobiol 2003, 55: 86–96.

    Article  CAS  PubMed  Google Scholar 

  32. Chen RZ, Akbarian S, Tudor M, Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 2001, 27: 327–331.

    Article  CAS  PubMed  Google Scholar 

  33. Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P, et al. Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 2008, 59: 947–958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Samaco RC, Mandel-Brehm C, Chao HT, Ward CS, Fyffe-Maricich SL, Ren J, et al. Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc Natl Acad Sci U S A 2009, 106: 21966–21971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, et al. A role for glia in the progression of Rett’s syndrome. Nature 2011, 475: 497–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Maezawa I, Swanberg S, Harvey D, LaSalle JM, Jin LW. Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J Neurosci 2009, 29: 5051–5061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tsujimura K, Abematsu M, Kohyama J, Namihira M, Nakashima K. Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2. Exp Neurol 2009, 219: 104–111.

    Article  CAS  PubMed  Google Scholar 

  38. Kishi N, Macklis JD. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci 2004, 27: 306–321.

    Article  CAS  PubMed  Google Scholar 

  39. Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 2002, 35: 243–254.

    Article  CAS  PubMed  Google Scholar 

  40. Cheval H, Guy J, Merusi C, De Sousa D, Selfridge J, Bird A. Postnatal Inactivation Reveals Enhanced Requirement for Mecp2 at Distinct Age Windows. Hum Mol Genet 2012, 21: 3806–3814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McGraw CM, Samaco RC, Zoghbi HY. Adult neural function requires MeCP2. Science 2011, 333: 186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Forbes-Lorman RM, Kurian JR, Auger AP. MeCP2 regulates GFAP expression within the developing brain. Brain Res 2014, 1543: 151–158.

    Article  CAS  PubMed  Google Scholar 

  43. Smrt RD, Eaves-Egenes J, Barkho BZ, Santistevan NJ, Zhao C, Aimone JB, et al. Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol Dis 2007, 27: 77–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rastegar M, Hotta A, Pasceri P, Makarem M, Cheung AY, Elliott S, et al. MECP2 isoform-specific vectors with regulated expression for Rett syndrome gene therapy. PLoS One 2009, 4: e6810.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Petazzi P, Akizu N, Garcia A, Estaras C, Martinez de Paz A, Rodriguez-Paredes M, et al. An increase in MECP2 dosage impairs neural tube formation. Neurobiol Dis 2014, 67: 49–56.

    Article  CAS  PubMed  Google Scholar 

  46. Cobb S, Guy J, Bird A. Reversibility of functional deficits in experimental models of Rett syndrome. Biochem Soc Trans 2010, 38: 498–506.

    Article  CAS  PubMed  Google Scholar 

  47. Marshak S, Meynard MM, De Vries YA, Kidane AH, Cohen-Cory S. Cell-autonomous alterations in dendritic arbor morphology and connectivity induced by overexpression of MeCP2 in Xenopus central neurons in vivo. PLoS One 2012, 7: e33153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ito M. Historical review of the significance of the cerebellum and the role of Purkinje cells in motor learning. Ann N Y Acad Sci 2002, 978: 273–288.

    Article  PubMed  Google Scholar 

  49. Millen KJ, Gleeson JG. Cerebellar development and disease. Curr Opin Neurobiol 2008, 18: 12–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Koeppen AH. The pathogenesis of spinocerebellar ataxia. Cerebellum 2005, 4: 62–73.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors sincerely thank Ya-Lin Huang, Ling-Mei Zhang and Shan-Zheng Yang (Shanghai Medical College, Fudan University) for their excellent technical assistance. This work was supported by a grant from the National Natural Science Foundation of China (81030020).

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Authors and Affiliations

  1. Department of Neurobiology, Institute of Biomedical Sciences, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Fang Liu, Jing-Jing Ni & Feng-Yan Sun

  2. Research Center on Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Feng-Yan Sun

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Correspondence to Feng-Yan Sun.

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Liu, F., Ni, JJ. & Sun, FY. Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development. Neurosci. Bull. 33, 1–16 (2017). https://doi.org/10.1007/s12264-016-0086-x

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  • DOI: https://doi.org/10.1007/s12264-016-0086-x

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