title: MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan.
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.
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Houston, Texas 77030, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Ward
authors.forename: E Melissa
authors.initials: EM
authors.lastname: Arvide
authors.forename: Teng-Wei
authors.initials: TW
authors.lastname: Huang
authors.forename: Jong
authors.initials: J
authors.lastname: Yoo
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Neul
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006339:Heart Rate / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009048:Motor Skills / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D012119:Respiration; D012125:Respiratory Center / Q000378:metabolism; D012249:Rhombencephalon / Q000378:metabolism
chemical_list: C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2