Regulation and function of stimulus-induced phosphorylation of MeCP2

Hongda LI, Qiang CHANG

PDF(569 KB)
PDF(569 KB)
Front. Biol. ›› 2014, Vol. 9 ›› Issue (5) : 367-375. DOI: 10.1007/s11515-014-1330-2
REVIEW
REVIEW

Regulation and function of stimulus-induced phosphorylation of MeCP2

Author information +
History +

Abstract

DNA methylation-dependent epigenetic regulation plays important roles in the development and function of the mammalian nervous system. MeCP2 is a key player in recognizing methylated DNA and interpreting the epigenetic information encoded in different DNA methylation patterns. Mutations in the MECP2 gene cause Rett syndrome, a devastating neurological disease that shares many features with autism. One interesting aspect of MeCP2 function is that it can be phosphorylated in response to diverse stimuli. Insights into the regulation and function of MeCP2 phosphorylation will help improve our understanding of how MeCP2 integrates environmental stimuli in neuronal nuclei to generate adaptive responses and may eventually lead to treatments for patients.

Keywords

MeCP2 / phosphorylation / Rett syndrome

Cite this article

Download citation ▾
Hongda LI, Qiang CHANG. Regulation and function of stimulus-induced phosphorylation of MeCP2. Front. Biol., 2014, 9(5): 367‒375 https://doi.org/10.1007/s11515-014-1330-2

References

[1]
Amir R E, Van den Veyver I B, Wan M, Tran C Q, Francke U, Zoghbi H Y (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet, 23(2): 185–188
CrossRef Pubmed Google scholar
[2]
Asaka Y, Jugloff D G, Zhang L, Eubanks J H, Fitzsimonds R M (2006). Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis, 21(1): 217–227
CrossRef Pubmed Google scholar
[3]
Ballas N, Lioy D T, Grunseich C, Mandel G (2009). Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci, 12(3): 311–317
CrossRef Pubmed Google scholar
[4]
Bracaglia G, Conca B, Bergo A, Rusconi L, Zhou Z, Greenberg M E, Landsberger N, Soddu S, Kilstrup-Nielsen C (2009). Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis. EMBO Rep, 10(12): 1327–1333
CrossRef Pubmed Google scholar
[5]
Buchthal B, Lau D, Weiss U, Weislogel J M, Bading H (2012). Nuclear calcium signaling controls methyl-CpG-binding protein 2 (MeCP2) phosphorylation on serine 421 following synaptic activity. J Biol Chem, 287(37): 30967–30974
CrossRef Pubmed Google scholar
[6]
Chahrour M, Jung S Y, Shaw C, Zhou X, Wong S T, Qin J, Zoghbi H Y (2008). MeCP2, a key contributor to neurological disease, activates and represses transcription. Science, 320(5880): 1224–1229
CrossRef Pubmed Google scholar
[7]
Chahrour M, Zoghbi H Y (2007). The story of Rett syndrome: from clinic to neurobiology. Neuron, 56(3): 422–437
CrossRef Pubmed Google scholar
[8]
Chao H T, Zoghbi H Y, Rosenmund C (2007). MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron, 56(1): 58–65
CrossRef Pubmed Google scholar
[9]
Chen W G, Chang Q, Lin Y, Meissner A, West A E, Griffith E C, Jaenisch R, Greenberg M E (2003). Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science, 302(5646): 885–889
CrossRef Pubmed Google scholar
[10]
Cheng T L, Wang Z, Liao Q, Zhu Y, Zhou W H, Xu W, Qiu Z (2014). MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex. Dev Cell, 28(5): 547–560
CrossRef Pubmed Google scholar
[11]
Cohen S, Gabel H W, Hemberg M, Hutchinson A N, Sadacca L A, Ebert D H, Harmin D A, Greenberg R S, Verdine V K, Zhou Z, Wetsel W C, West A E, Greenberg M E (2011). Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron, 72(1): 72–85
CrossRef Pubmed Google scholar
[12]
Collins A L, Levenson J M, Vilaythong A P, Richman R, Armstrong D L, Noebels J L, David Sweatt J, Zoghbi H Y (2004). Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet, 13(21): 2679–2689
CrossRef Pubmed Google scholar
[13]
Deng J V, Rodriguiz R M, Hutchinson A N, Kim I H, Wetsel W C, West A E (2010). MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants. Nat Neurosci, 13(9): 1128–1136
CrossRef Pubmed Google scholar
[14]
Deng J V, Wan Y, Wang X, Cohen S, Wetsel W.C, Greenberg M E, Kenny P J, Calakos N, West A E (2014). MeCP2 phosphorylation limits psychostimulant-induced behavioral and neuronal plasticity. J Neurosci, 34: 4519–4527
[15]
Derecki N C, Cronk J C, Lu Z, Xu E, Abbott S B, Guyenet P G, Kipnis J (2012). Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature, 484(7392): 105–109
CrossRef Pubmed Google scholar
[16]
Ebert D H, Gabel H W, Robinson N D, Kastan N R, Hu L S, Cohen S, Navarro A J, Lyst M J, Ekiert R, Bird A P, Greenberg M E (2013). Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature, 499(7458): 341–345
Pubmed
[17]
Fyffe S L, Neul J L, Samaco R C, Chao H T, Ben-Shachar S, Moretti P, McGill B E, Goulding E H, Sullivan E, Tecott L H, Zoghbi H Y (2008). Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron, 59(6): 947–958
CrossRef Pubmed Google scholar
[18]
Géranton S M, Fratto V, Tochiki K K, Hunt S P (2008). Descending serotonergic controls regulate inflammation-induced mechanical sensitivity and methyl-CpG-binding protein 2 phosphorylation in the rat superficial dorsal horn. Mol Pain, 4(1): 35
CrossRef Pubmed Google scholar
[19]
Géranton S M, Morenilla-Palao C, Hunt S P (2007). A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states. J Neurosci, 27: 6163–6173
[20]
Gonzales M L, Adams S, Dunaway K W, LaSalle J M (2012). Phosphorylation of distinct sites in MeCP2 modifies cofactor associations and the dynamics of transcriptional regulation. Mol Cell Biol, 32(14): 2894–2903
CrossRef Pubmed Google scholar
[21]
Hagberg B (1985). Rett’s syndrome: prevalence and impact on progressive severe mental retardation in girls. Acta Paediatr Scand, 74(3): 405–408
CrossRef Pubmed Google scholar
[22]
Hutchinson A N, Deng J V, Aryal D K, Wetsel W C, West A E (2012a). Differential regulation of MeCP2 phosphorylation in the CNS by dopamine and serotonin. Neuropsychopharmacology, 37: 321–337
[23]
Hutchinson A N, Deng, J V, Cohen S, West A E (2012b). Phosphorylation of MeCP2 at Ser421 contributes to chronic antidepressant action. J Neurosci, 32: 14355–14363
[24]
Jones P L, Veenstra G J, Wade P A, Vermaak D, Kass S U, Landsberger N, Strouboulis J, Wolffe A P (1998). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet, 19(2): 187–191
CrossRef Pubmed Google scholar
[25]
Lewis J D, Meehan R R, Henzel W J, Maurer-Fogy I, Jeppesen P, Klein F, Bird A (1992). Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell, 69(6): 905–914
CrossRef Pubmed Google scholar
[26]
Li H, Zhong X, Chau K F, Williams E C, Chang Q (2011). Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory. Nat Neurosci, 14(8): 1001–1008
CrossRef Pubmed Google scholar
[27]
Lioy D T, Garg S K, Monaghan C E, Raber J, Foust K D, Kaspar B K, Hirrlinger P G, Kirchhoff F, Bissonnette J M, Ballas N, Mandel G (2011). A role for glia in the progression of Rett’s syndrome. Nature, 475(7357): 497–500
CrossRef Pubmed Google scholar
[28]
Lyst M J, Ekiert R, Ebert D H, Merusi C, Nowak J, Selfridge J, Guy J, Kastan N R, Robinson N D, de Lima Alves F, Rappsilber J, Greenberg M E, Bird A (2013). Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat Neurosci, 16(7): 898–902
CrossRef Pubmed Google scholar
[29]
Mao L M, Horton E, Guo M L, Xue B, Jin D Z, Fibuch E E, Wang J Q (2011). Cocaine increases phosphorylation of MeCP2 in the rat striatum in vivo: a differential role of NMDA receptors. Neurochem Int, 59(5): 610–617
CrossRef Pubmed Google scholar
[30]
Miyake K, Nagai K (2007). Phosphorylation of methyl-CpG binding protein 2 (MeCP2) regulates the intracellular localization during neuronal cell differentiation. Neurochem Int, 50(1): 264–270
CrossRef Pubmed Google scholar
[31]
Moretti P, Levenson J.M, Battaglia F, Atkinson R, Teague R, Antalffy B, Armstrong D, Arancio O, Sweatt J D, Zoghbi H Y(2006). Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci, 26: 319–327
[32]
Murgatroyd C, Patchev A V, Wu Y, Micale V, Bockmühl Y, Fischer D, Holsboer F, Wotjak C T, Almeida O F, Spengler D (2009). Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci, 12(12): 1559–1566
CrossRef Pubmed Google scholar
[33]
Nagarajan R P, Hogart A R, Gwye Y, Martin M R, LaSalle J M (2006). Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics: official journal of the DNA Methylation Society, 1: e1–11
[34]
Nagarajan R P, Patzel K A, Martin M, Yasui D H, Swanberg S E, Hertz-Picciotto I, Hansen R L, Van de Water J, Pessah I N, Jiang R, Robinson W P, LaSalle J M (2008). MECP2 promoter methylation and X chromosome inactivation in autism. Autism Res, 1: 169–178
[35]
Nan X, Campoy F J, Bird A (1997). MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell, 88(4): 471–481
CrossRef Pubmed Google scholar
[36]
Nan X, Ng H H, Johnson C A, Laherty C D, Turner B M, Eisenman R N, Bird A (1998). Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature, 393(6683): 386–389
CrossRef Pubmed Google scholar
[37]
Nguyen M V, Felice C A, Du F, Covey M V, Robinson J K, Mandel G, Ballas N (2013). Oligodendrocyte lineage cells contribute unique features to Rett syndrome neuropathology. J Neurosci, 33: 18764–18774
[38]
Qiu Z, Sylwestrak E L, Lieberman D N, Zhang Y, Liu X Y, Ghosh A (2012). The Rett syndrome protein MeCP2 regulates synaptic scaling. J Neurosci, 32: 989–994
[39]
Ramocki M B, Peters S U, Tavyev Y J, Zhang F, Carvalho C M, Schaaf C P, Richman R, Fang P, Glaze D G, Lupski J R, Zoghbi H Y (2009). Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann Neurol, 66(6): 771–782
CrossRef Pubmed Google scholar
[40]
Rexach J E, Rogers C J, Yu S H, Tao J, Sun Y E, Hsieh-Wilson L C (2010). Quantification of O-glycosylation stoichiometry and dynamics using resolvable mass tags. Nat Chem Biol, 6(9): 645–651
CrossRef Pubmed Google scholar
[41]
Skene P J, Illingworth R S, Webb S, Kerr A R, James K D, Turner D J, Andrews R, Bird A P (2010). Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol Cell, 37(4): 457–468
CrossRef Pubmed Google scholar
[42]
Szulwach K E, Li X, Li Y, Song C X, Wu H, Dai Q, Irier H, Upadhyay A K, Gearing M, Levey A I, Vasanthakumar A, Godley L A, Chang Q, Cheng X, He C, Jin P (2011). 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci, 14(12): 1607–1616
CrossRef Pubmed Google scholar
[43]
Tao J, Hu K, Chang Q, Wu H, Sherman N E, Martinowich K, Klose R J, Schanen C, Jaenisch R, Wang W, Sun Y E (2009). Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function. Proc Natl Acad Sci USA, 106(12): 4882–4887
CrossRef Pubmed Google scholar
[44]
Xi C Y, Ma H W, Lu Y, Zhao Y J, Hua T Y, Zhao Y, Ji Y H (2007). MeCP2 gene mutation analysis in autistic boys with developmental regression. Psychiatr Genet, 17(2): 113–116
CrossRef Pubmed Google scholar
[45]
Zhong X, Li H, Chang Q (2012). MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5. J Neurosci, 32: 12841–12847
[46]
Zhou Z, Hong E J, Cohen S, Zhao W N, Ho H Y, Schmidt L, Chen W G, Lin Y, Savner E, Griffith E C, Hu L, Steen J A, Weitz C J, Greenberg M E (2006). Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron, 52(2): 255–269
CrossRef Pubmed Google scholar

Acknowledgements

H.L. was supported by a pre-doctoral fellowship from the Stem Cell and Regenerative Medicine Center at the University of Wisconsin-Madison and a graduate student fellowship from the Friends of the Waisman Center. Q.C. was supported by a Young Investigator Award from NARSAD. This work was partially supported by grants from NICHD (R01 HD064743 and R21 HD066560 to Q.C. and P30 HD03352 to the Waisman Center).

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg
PDF(569 KB)

Accesses

Citations

Detail

Sections
Recommended

/