Adult neural function requires MeCP2 - PubMed (original) (raw)

Adult neural function requires MeCP2

Christopher M McGraw et al. Science. 2011.

Abstract

Rett syndrome (RTT) is a postnatal neurological disorder caused by mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2 (MeCP2). The onset of RTT symptoms during early life together with findings suggesting neurodevelopmental abnormalities in RTT and mouse models of RTT raised the question of whether maintaining MeCP2 function exclusively during early life might protect against disease. We show by using an inducible model of RTT that deletion of Mecp2 in adult mice recapitulates the germline knock-out phenotype, underscoring the ongoing role of MeCP2 in adult neurological function. Moreover, unlike the effects of other epigenetic instructions programmed during early life, the effects of early MeCP2 function are lost soon after its deletion. These findings suggest that therapies for RTT must be maintained throughout life.

PubMed Disclaimer

Figures

Figure 1. Adult deletion of Mecp2 recapitulates germline knock-out

(A–B) MeCP2 is depleted in adult knock-out (AKO) mice by western blot of brain lysates (A, N= 3–4 mice per genotype), and by immunofluorescence in cerebellum (B). Scale bar = 50um. (C) AKO mice display symptoms of disease. N= 6–12 per genotype. (D) AKO mice develop motor and learning impairments similar to germline Mecp2null/y (KO) mice. N=10–26 per genotype. (E) Sst and Grin2a mRNA levels are altered in AKO mice. N = 4–12 per genotype. (F) AKO mice die prematurely (left) similar to KO mice (right). N=10–26 per genotype. Data presented as mean ± s.e.m. (*) p<0.05, (**) p<0.01, or (***) p<0.001.

Cited by

The Molecular Functions of MeCP2 in Rett Syndrome Pathology.
Sharifi O, Yasui DH. Sharifi O, et al. Front Genet. 2021 Apr 23;12:624290. doi: 10.3389/fgene.2021.624290. eCollection 2021. Front Genet. 2021. PMID: 33968128 Free PMC article. Review.
The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes.
Scaramuzza L, De Rocco G, Desiato G, Cobolli Gigli C, Chiacchiaretta M, Mirabella F, Pozzi D, De Simone M, Conforti P, Pagani M, Benfenati F, Cesca F, Bedogni F, Landsberger N. Scaramuzza L, et al. EMBO Mol Med. 2021 Apr 9;13(4):e12433. doi: 10.15252/emmm.202012433. Epub 2021 Mar 5. EMBO Mol Med. 2021. PMID: 33665914 Free PMC article.
The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1.
Cukier HN, Lee JM, Ma D, Young JI, Mayo V, Butler BL, Ramsook SS, Rantus JA, Abrams AJ, Whitehead PL, Wright HH, Abramson RK, Haines JL, Cuccaro ML, Pericak-Vance MA, Gilbert JR. Cukier HN, et al. Autism Res. 2012 Dec;5(6):385-97. doi: 10.1002/aur.1251. Epub 2012 Oct 10. Autism Res. 2012. PMID: 23055267 Free PMC article.
Vitamin D Supplementation Rescues Aberrant NF-κB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in Mecp2 Mutant Mice.
Ribeiro MC, Moore SM, Kishi N, Macklis JD, MacDonald JL. Ribeiro MC, et al. eNeuro. 2020 May 22;7(3):ENEURO.0167-20.2020. doi: 10.1523/ENEURO.0167-20.2020. Print 2020 May/Jun. eNeuro. 2020. PMID: 32393583 Free PMC article.
5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging.
Szulwach KE, Li X, Li Y, Song CX, Wu H, Dai Q, Irier H, Upadhyay AK, Gearing M, Levey AI, Vasanthakumar A, Godley LA, Chang Q, Cheng X, He C, Jin P. Szulwach KE, et al. Nat Neurosci. 2011 Oct 30;14(12):1607-16. doi: 10.1038/nn.2959. Nat Neurosci. 2011. PMID: 22037496 Free PMC article.

References

1. Chahrour M, Zoghbi HY. Neuron. 2007;56:422–437. - PubMed
1. Guy J, Gan J, Selfridge J, Cobb S, Bird A. Science. 2007;315:1143–1147. - PMC - PubMed
1. Guy J, Hendrich B, Holmes M, Martin JE, Bird A. Nat Genet. 2001;27:322–326. - PubMed
1. Hayashi S, McMahon AP. Developmental Biology. 2002;244:305–318. - PubMed
1. Chahrour M, et al. Science. 2008;320:1224–1229. - PMC - PubMed

Adult neural function requires MeCP2 - PubMed (original) (raw)