title: Progressive Changes in a Distributed Neural Circuit Underlie Breathing Abnormalities in Mice Lacking MeCP2.
abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Severe breathing abnormalities are common in RTT and are reproduced in mouse models of RTT. Previously, we found that removing MeCP2 from the brainstem and spinal cord in mice caused early lethality and abnormal breathing. To determine whether loss of MeCP2 in functional components of the respiratory network causes specific breathing disorders, we used the Cre/LoxP system to differentially manipulate MeCP2 expression throughout the brainstem respiratory network, specifically within HoxA4-derived tissues, which include breathing control circuitry within the nucleus tractus solitarius and the caudal part of ventral respiratory column but do not include more rostral parts of the breathing control circuitry. To determine whether respiratory phenotypes manifested in animals with MeCP2 removed from specific pons medullary respiratory circuits, we performed whole-body plethysmography and electrophysiological recordings from in vitro brainstem slices from mice lacking MeCP2 in different circuits. Our results indicate that MeCP2 expression in the medullary respiratory network is sufficient for normal respiratory rhythm and preventing apnea. However, MeCP2 expression within components of the breathing circuitry rostral to the HoxA4 domain are neither sufficient to prevent the hyperventilation nor abnormal hypoxic ventilatory response. Surprisingly, we found that MeCP2 expression in the HoxA4 domain alone is critical for survival. Our study reveals that MeCP2 is differentially required in select respiratory components for different aspects of respiratory functions, and collectively for the integrity of this network functions to maintain proper respiration.
  
  
  
  Breathing abnormalities are a significant clinical feature in Rett syndrome and are robustly reproduced in the mouse models of this disease. Previous work has established that alterations in the function of MeCP2, the protein encoded by the gene mutated in Rett syndrome, within the hindbrain are critical for control of normal breathing. Here we show that MeCP2 function plays distinct roles in specific brainstem regions in the genesis of various aspects of abnormal breathing. This provides insight into the pathogenesis of these breathing abnormalities in Rett syndrome, which could be used to target treatments to improve these symptoms. Furthermore, it provides further knowledge about the fundamental neural circuits that control breathing.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030.
authors.forename: Teng-Wei
authors.identifier: 0000-0002-8604-1262
authors.initials: TW
authors.lastname: Huang
authors.affiliation: Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030.
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Kochukov
authors.affiliation: Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, Department of Neurosciences, University of California-San Diego, La Jolla, California 92093, and.
authors.forename: Christopher S
authors.identifier: 0000-0002-3445-6327
authors.initials: CS
authors.lastname: Ward
authors.affiliation: Department of Neurosciences, University of California-San Diego, La Jolla, California 92093, and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Merritt
authors.affiliation: Department of Neurosciences, University of California-San Diego, La Jolla, California 92093, and.
authors.forename: Kaitlin
authors.identifier: 0000-0003-3833-2468
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Department of Neurosciences, University of California-San Diego, La Jolla, California 92093, and.
authors.forename: Tiffani
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, Department of Neurosciences, University of California-San Diego, La Jolla, California 92093, and Department of Molecular and Human Genetics, Baylor College of Medicine, Department of Neuroscience, and.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Arenkiel
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, Department of Neurosciences, University of California-San Diego, La Jolla, California 92093, and Department of Molecular and Human Genetics, Baylor College of Medicine, Department of Neuroscience, and Departments of Pediatrics, Neurology, and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030 jneul@ucsd.edu.
authors.forename: Jeffrey L
authors.identifier: 0000-0002-5628-5872
authors.initials: JL
authors.lastname: Neul
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism / Q000502:physiology*; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D012119:Respiration; D015518:Rett Syndrome / Q000235:genetics / Q000503:physiopathology*; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C484111:Hoxa4 protein, mouse; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D014157:Transcription Factors
keywords: HoxA4; HoxB1; MECP2; Rett; breathing