{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:26:14Z","timestamp":1788315974099,"version":"build-2803163510"},"reference-count":57,"publisher":"Society for Neuroscience","issue":"20","license":[{"start":{"date-parts":[[2016,11,18]],"date-time":"2016-11-18T00:00:00Z","timestamp":1479427200000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2016,5,18]]},"abstract":"<jats:p>\n                    Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in\n                    <jats:italic>Methyl-CpG-binding protein 2<\/jats:italic>\n                    (\n                    <jats:italic>MECP2<\/jats:italic>\n                    ). 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\n                    <jats:italic>in vitro<\/jats:italic>\n                    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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>\n                    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.\n                  <\/jats:p>","DOI":"10.1523\/jneurosci.2330-15.2016","type":"journal-article","created":{"date-parts":[[2016,5,18]],"date-time":"2016-05-18T12:14:50Z","timestamp":1463573690000},"page":"5572-5586","source":"Crossref","is-referenced-by-count":31,"title":["Progressive Changes in a Distributed Neural Circuit Underlie Breathing Abnormalities in Mice Lacking MeCP2"],"prefix":"10.1523","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8604-1262","authenticated-orcid":false,"given":"Teng-Wei","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail Y.","family":"Kochukov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3445-6327","authenticated-orcid":false,"given":"Christopher S.","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Merritt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3833-2468","authenticated-orcid":false,"given":"Kaitlin","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffani","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin R.","family":"Arenkiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5628-5872","authenticated-orcid":false,"given":"Jeffrey L.","family":"Neul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2016,5,18]]},"reference":[{"key":"2023041803191485000_36.20.5572.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2008.07.014"},{"key":"2023041803191485000_36.20.5572.2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.10323"},{"key":"2023041803191485000_36.20.5572.3","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1242\/dev.117.3.823","article-title":"Sequences 5\u2032 of the homeobox of the Hox-1.4 gene direct tissue-specific expression of lacZ during mouse development","volume":"117","author":"Behringer","year":"1993","journal-title":"Development"},{"key":"2023041803191485000_36.20.5572.4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.1995.75.1.1","article-title":"Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters","volume":"75","author":"Bianchi","year":"1995","journal-title":"Physiol Rev"},{"key":"2023041803191485000_36.20.5572.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2014.02.043"},{"key":"2023041803191485000_36.20.5572.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature09582"},{"key":"2023041803191485000_36.20.5572.7","doi-asserted-by":"publisher","DOI":"10.1038\/85906"},{"key":"2023041803191485000_36.20.5572.8","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1152\/physrev.1979.59.4.1105","article-title":"Neurogenesis of respiratory rhythm in the mammal","volume":"59","author":"Cohen","year":"1979","journal-title":"Physiol Rev"},{"key":"2023041803191485000_36.20.5572.9","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00024.2014"},{"key":"2023041803191485000_36.20.5572.10","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4639-10.2011"},{"key":"2023041803191485000_36.20.5572.11","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903470106"},{"key":"2023041803191485000_36.20.5572.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.04981.x"},{"key":"2023041803191485000_36.20.5572.13","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1152\/jappl.1986.61.3.906","article-title":"Ventilatory response to sustained hypoxia in normal adults","volume":"61","author":"Easton","year":"1986","journal-title":"J Appl Physiol"},{"key":"2023041803191485000_36.20.5572.14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0092169"},{"key":"2023041803191485000_36.20.5572.15","unstructured":"Feldman JL Smith JC (1995) in Regulation of breathing, Neural control of respiratory pattern in mammals: an overview, eds Dempsey JA Pack AI (Marcel Dekker, New York), pp 39\u201369."},{"key":"2023041803191485000_36.20.5572.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.07.030"},{"key":"2023041803191485000_36.20.5572.17","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-53825-3.00008-5"},{"key":"2023041803191485000_36.20.5572.18","doi-asserted-by":"publisher","DOI":"10.1038\/85899"},{"key":"2023041803191485000_36.20.5572.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.1138389"},{"key":"2023041803191485000_36.20.5572.20","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.020131"},{"key":"2023041803191485000_36.20.5572.21","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00237.2010"},{"key":"2023041803191485000_36.20.5572.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.06.027"},{"key":"2023041803191485000_36.20.5572.23","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1152\/jn.2001.85.4.1772","article-title":"Isolation of the kernel for respiratory rhythm generation in a novel preparation: the pre-Botzinger complex \u201cisland.\u201d","volume":"85","author":"Johnson","year":"2001","journal-title":"J Neurophysiol"},{"key":"2023041803191485000_36.20.5572.24","doi-asserted-by":"publisher","DOI":"10.1136\/adc.85.1.29"},{"key":"2023041803191485000_36.20.5572.25","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000223318.28938.45"},{"key":"2023041803191485000_36.20.5572.26","first-page":"71","article-title":"Rett syndrome: analysis of deaths in the British survey","volume":"6","author":"Kerr","year":"1997","journal-title":"Eur Child Adolesc Psychiatry"},{"key":"2023041803191485000_36.20.5572.27","doi-asserted-by":"publisher","DOI":"10.1038\/22540"},{"key":"2023041803191485000_36.20.5572.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2005.10.037"},{"key":"2023041803191485000_36.20.5572.29","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002982"},{"key":"2023041803191485000_36.20.5572.30","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00826.2007"},{"key":"2023041803191485000_36.20.5572.31","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.038141"},{"key":"2023041803191485000_36.20.5572.32","doi-asserted-by":"publisher","DOI":"10.1038\/nn1357"},{"key":"2023041803191485000_36.20.5572.33","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22124"},{"key":"2023041803191485000_36.20.5572.34","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1869-07.2007"},{"key":"2023041803191485000_36.20.5572.35","unstructured":"Paxinos G Franklin K (2008) The mouse brain in stereotaxic coordinates (Elsevier, Amsterdam), Ed 3."},{"key":"2023041803191485000_36.20.5572.36","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt111"},{"key":"2023041803191485000_36.20.5572.37","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv030"},{"key":"2023041803191485000_36.20.5572.38","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021258"},{"key":"2023041803191485000_36.20.5572.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2013.06.022"},{"key":"2023041803191485000_36.20.5572.40","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2951-12.2012"},{"key":"2023041803191485000_36.20.5572.41","doi-asserted-by":"crossref","unstructured":"Richter DW (1996) in Comprehensive human physiology, Vol II, Neural regulation of respiration: rhythmogenesis and afferent control, eds Gregor R Windhorst U (Springer, Berlin), pp 2079\u20132095.","DOI":"10.1007\/978-3-642-60946-6_106"},{"key":"2023041803191485000_36.20.5572.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2007.06.009"},{"key":"2023041803191485000_36.20.5572.43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912257106"},{"key":"2023041803191485000_36.20.5572.44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2008.01005.x"},{"key":"2023041803191485000_36.20.5572.45","doi-asserted-by":"publisher","DOI":"10.1037\/0021-9010.76.5.628"},{"key":"2023041803191485000_36.20.5572.46","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00985.2007"},{"key":"2023041803191485000_36.20.5572.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2012.11.004"},{"key":"2023041803191485000_36.20.5572.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2010.11.065"},{"key":"2023041803191485000_36.20.5572.49","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.119966"},{"key":"2023041803191485000_36.20.5572.50","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00012.2009"},{"key":"2023041803191485000_36.20.5572.51","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2014.079798"},{"key":"2023041803191485000_36.20.5572.52","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4373-05.2005"},{"key":"2023041803191485000_36.20.5572.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2009.05.013"},{"key":"2023041803191485000_36.20.5572.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2010.07.006"},{"key":"2023041803191485000_36.20.5572.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2009.12.009"},{"key":"2023041803191485000_36.20.5572.56","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0057-11.2011"},{"key":"2023041803191485000_36.20.5572.57","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000238302.84552.d0"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.2330-15.2016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T06:33:49Z","timestamp":1681799629000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.2330-15.2016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,18]]},"references-count":57,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2016,5,18]]},"published-print":{"date-parts":[[2016,5,18]]}},"alternative-id":["10.1523\/JNEUROSCI.2330-15.2016"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.2330-15.2016","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.726365937.793526846","asserted-by":"object"}]},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,18]]}}}