MeCP2 is Critical Within HoxB1-derived Tissues of Mice for Normal Lifespan

Overview

Journal J Neurosci

Specialty Neurology

Date 2011 Jul 15

PMID 21753013

Citations 52

Authors

Christopher S Ward

E Melissa Arvide

Teng-Wei Huang

Jong Yoo

Jeffrey L Noebels

Jeffrey L Neul

Affiliations

Soon will be listed here.

Abstract

Rett syndrome is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), a transcriptional regulator. In addition to cognitive, communication, and motor problems, affected individuals have abnormalities in autonomic function and respiratory control that may contribute to premature lethality. Mice lacking Mecp2 die early and recapitulate the autonomic and respiratory phenotypes seen in humans. The association of autonomic and respiratory deficits with premature death suggests that Mecp2 is critical within autonomic and respiratory control centers for survival. To test this, we compared the autonomic and respiratory phenotypes of mice with a null allele of Mecp2 to mice with Mecp2 removed from their brainstem and spinal cord. We found that MeCP2 is necessary within the brainstem and spinal cord for normal lifespan, normal control of heart rate, and respiratory response to hypoxia. Restoration of MeCP2 in a subset of the cells in this same region is sufficient to rescue abnormal heart rate and abnormal respiratory response to hypoxia. Furthermore, restoring MeCP2 function in neural centers critical for autonomic and respiratory function alleviates the lethality associated with loss of MeCP2 function, supporting the notion of targeted therapy toward treating Rett syndrome.

Citing Articles

Transgenic rodents as dynamic models for the study of respiratory rhythm generation and modulation: a scoping review and a bibliometric analysis.

Olmos-Pastoresa C, Vazquez-Mendoza E, Lopez-Meraz M, Perez-Estudillo C, Beltran-Parrazal L, Morgado-Valle C Front Physiol. 2024; 14:1295632.

PMID: 38179140 PMC: 10764557. DOI: 10.3389/fphys.2023.1295632.

Mecp2 deletion results in profound alterations of developmental and adult functional connectivity.

Rahn R, Yen A, Chen S, Gaines S, Bice A, Brier L Cereb Cortex. 2023; 33(12):7436-7453.

PMID: 36897048 PMC: 10267622. DOI: 10.1093/cercor/bhad050.

Breathing Abnormalities During Sleep and Wakefulness in Rett Syndrome: Clinical Relevance and Paradoxical Relationship With Circulating Pro-oxidant Markers.

Leoncini S, Signorini C, Boasiako L, Scandurra V, Hayek J, Ciccoli L Front Neurol. 2022; 13:833239.

PMID: 35422749 PMC: 9001904. DOI: 10.3389/fneur.2022.833239.

Rett syndrome: think outside the (skull) box.

Borloz E, Villard L, Roux J Fac Rev. 2021; 10:59.

PMID: 34308425 PMC: 8265562. DOI: 10.12703/r/10-59.

Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome.

Collins B, Merritt J, Erickson K, Neul J Genes Brain Behav. 2021; 21(1):e12739.

PMID: 33942492 PMC: 8563491. DOI: 10.1111/gbb.12739.

References

Schule B, Armstrong D, Vogel H, Oviedo A, Francke U . Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin Genet. 2008; 74(2):116-26. DOI: 10.1111/j.1399-0004.2008.01005.x. View

West M, Slomianka L, Gundersen H . Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat Rec. 1991; 231(4):482-97. DOI: 10.1002/ar.1092310411. View

Arenkiel B, Gaufo G, Capecchi M . Hoxb1 neural crest preferentially form glia of the PNS. Dev Dyn. 2003; 227(3):379-86. DOI: 10.1002/dvdy.10323. View

Lazarenko R, Milner T, DePuy S, Stornetta R, West G, Kievits J . Acid sensitivity and ultrastructure of the retrotrapezoid nucleus in Phox2b-EGFP transgenic mice. J Comp Neurol. 2009; 517(1):69-86. PMC: 2826801. DOI: 10.1002/cne.22136. View

Weese-Mayer D, Lieske S, Boothby C, Kenny A, Bennett H, Silvestri J . Autonomic nervous system dysregulation: breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome. Pediatr Res. 2006; 60(4):443-9. DOI: 10.1203/01.pdr.0000238302.84552.d0. View

Pratte M, Panayotis N, Ghata A, Villard L, Roux J . Progressive motor and respiratory metabolism deficits in post-weaning Mecp2-null male mice. Behav Brain Res. 2010; 216(1):313-20. DOI: 10.1016/j.bbr.2010.08.011. View

Samaco R, Mandel-Brehm C, Chao H, Ward C, Fyffe-Maricich S, Ren J . 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(51):21966-71. PMC: 2799790. DOI: 10.1073/pnas.0912257106. View

Guy J, Hendrich B, Holmes M, Martin J, Bird A . A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 2001; 27(3):322-6. DOI: 10.1038/85899. View

Rohdin M, Fernell E, Eriksson M, Albage M, Lagercrantz H, Katz-Salamon M . Disturbances in cardiorespiratory function during day and night in Rett syndrome. Pediatr Neurol. 2007; 37(5):338-44. DOI: 10.1016/j.pediatrneurol.2007.06.009. View

10.

Amir R, Van den Veyver I, Wan M, Tran C, Francke U, Zoghbi H . Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999; 23(2):185-8. DOI: 10.1038/13810. View

11.

Medrihan L, Tantalaki E, Aramuni G, Sargsyan V, Dudanova I, Missler M . Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome. J Neurophysiol. 2007; 99(1):112-21. DOI: 10.1152/jn.00826.2007. View

12.

Soriano P . Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999; 21(1):70-1. DOI: 10.1038/5007. View

13.

Stornetta R, Rosin D, Wang H, Sevigny C, Weston M, Guyenet P . A group of glutamatergic interneurons expressing high levels of both neurokinin-1 receptors and somatostatin identifies the region of the pre-Bötzinger complex. J Comp Neurol. 2003; 455(4):499-512. DOI: 10.1002/cne.10504. View

14.

Guy J, Gan J, Selfridge J, Cobb S, Bird A . Reversal of neurological defects in a mouse model of Rett syndrome. Science. 2007; 315(5815):1143-7. PMC: 7610836. DOI: 10.1126/science.1138389. View

15.

Ogier M, Wang H, Hong E, Wang Q, Greenberg M, Katz D . Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome. J Neurosci. 2007; 27(40):10912-7. PMC: 6672830. DOI: 10.1523/JNEUROSCI.1869-07.2007. View

16.

Glaze D, Percy A, Skinner S, Motil K, Neul J, Barrish J . Epilepsy and the natural history of Rett syndrome. Neurology. 2010; 74(11):909-12. PMC: 2836870. DOI: 10.1212/WNL.0b013e3181d6b852. View

17.

Adachi M, Autry A, Covington 3rd H, Monteggia L . MeCP2-mediated transcription repression in the basolateral amygdala may underlie heightened anxiety in a mouse model of Rett syndrome. J Neurosci. 2009; 29(13):4218-27. PMC: 3005250. DOI: 10.1523/JNEUROSCI.4225-08.2009. View

18.

Shahbazian M, Young J, Spencer C, Antalffy B, Noebels J, Armstrong D . Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron. 2002; 35(2):243-54. DOI: 10.1016/s0896-6273(02)00768-7. View

19.

Neul J, Kaufmann W, Glaze D, Christodoulou J, Clarke A, Bahi-Buisson N . Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010; 68(6):944-50. PMC: 3058521. DOI: 10.1002/ana.22124. View

20.

Guideri F, Acampa M, Hayek G, Zappella M, Di Perri T . Reduced heart rate variability in patients affected with Rett syndrome. A possible explanation for sudden death. Neuropediatrics. 1999; 30(3):146-8. DOI: 10.1055/s-2007-973480. View