{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:36:29Z","timestamp":1790472989319,"version":"4.1.0"},"reference-count":36,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2017,1,15]],"date-time":"2017-01-15T00:00:00Z","timestamp":1484438400000},"content-version":"vor","delay-in-days":380,"URL":"http:\/\/www.biologists.com\/user-licence-1-1"}],"funder":[{"DOI":"10.13039\/100006955","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-NS064993"],"award-info":[{"award-number":["R01-NS064993"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HG003988"],"award-info":[{"award-number":["R01-HG003988"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HG006997"],"award-info":[{"award-number":["R01-HG006997"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01-DE024427"],"award-info":[{"award-number":["U01-DE024427"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F32-DE025519"],"award-info":[{"award-number":["F32-DE025519"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R90-DE023059"],"award-info":[{"award-number":["R90-DE023059"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002879","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MEF-140891"],"award-info":[{"award-number":["MEF-140891"]}],"id":[{"id":"10.13039\/501100002879","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000015","name":"U.S. Department of Energy","doi-asserted-by":"publisher","award":["DE-AC02-05CH11231"],"award-info":[{"award-number":["DE-AC02-05CH11231"]}],"id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L009986\/1"],"award-info":[{"award-number":["MR\/L009986\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:p>Hmx1 encodes a homeodomain transcription factor expressed in the developing lateral craniofacial mesenchyme, retina and sensory ganglia. Mutation or mis-regulation of Hmx1 underlies malformations of the eye and external ear in multiple species. Deletion or insertional duplication of an evolutionarily conserved region (ECR) downstream of Hmx1 has recently been described in rat and cow, respectively. Here we demonstrate the impact of Hmx1 loss is greater than previously appreciated, with a variety of lateral cranioskeletal defects, auriculofacial nerve deficits, and duplication of the caudal region of the external ear. Using a transgenic approach, we demonstrate that a 594bp sequence encompassing the ECR recapitulates specific aspects of the endogenous Hmx1 lateral facial expression pattern. Moreover, we show that Hoxa2, Meis and Pbx act cooperatively on the ECR, via a core 32bp sequence, to regulate Hmx1 expression. These studies highlight the conserved role for Hmx1 in BA2-derived tissues and provide an entry point to better understand the causes of the frequent lateral facial birth defects in humans.<\/jats:p>","DOI":"10.1242\/dev.133736","type":"journal-article","created":{"date-parts":[[2016,6,11]],"date-time":"2016-06-11T04:31:44Z","timestamp":1465619504000},"source":"Crossref","is-referenced-by-count":13,"title":["A distal 594bp ECR specifies <i>Hmx1<\/i> expression in pinna and lateral facial morphogenesis and is regulated by Hox-Pbx-Meis"],"prefix":"10.1242","author":[{"given":"Jessica M.","family":"Rosin","sequence":"first","affiliation":[{"name":"Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA"},{"name":"Department of Oral Health Sciences, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0703-7258","authenticated-orcid":false,"given":"Liza L.","family":"Cox","sequence":"additional","affiliation":[{"name":"Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA"},{"name":"Department of Pediatrics (Craniofacial Medicine), University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Rolfe","sequence":"additional","affiliation":[{"name":"Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Latorre","sequence":"additional","affiliation":[{"name":"School of Dentistry, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0667-9355","authenticated-orcid":false,"given":"Jennifer A.","family":"Akiyama","sequence":"additional","affiliation":[{"name":"Functional Genomics Department, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4130-7784","authenticated-orcid":false,"given":"Axel","family":"Visel","sequence":"additional","affiliation":[{"name":"Functional Genomics Department, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"name":"DOE Joint Genome Institute, Walnut Creek, CA, USA"},{"name":"School of Natural Sciences, University of California, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kuramoto","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7103-4932","authenticated-orcid":false,"given":"Nicoletta","family":"Bobola","sequence":"additional","affiliation":[{"name":"School of Dentistry, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5499-6788","authenticated-orcid":false,"given":"Eric E.","family":"Turner","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-5528","authenticated-orcid":false,"given":"Timothy C.","family":"Cox","sequence":"additional","affiliation":[{"name":"Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA"},{"name":"Department of Oral Health Sciences, University of Washington, Seattle, WA, USA"},{"name":"Department of Pediatrics (Craniofacial Medicine), University of Washington, Seattle, WA, USA"},{"name":"Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608362817000_DEV133736C1","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1016\/j.ajhg.2008.02.015","article-title":"A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family","volume":"82","author":"Alasti","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"2021042608362817000_DEV133736C2","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/978-1-4939-1242-1_14","article-title":"Chromatin immunoprecipitation and chromatin immunoprecipitation with massively parallel sequencing on mouse embryonic tissue","volume":"1196","author":"Amin","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"2021042608362817000_DEV133736C3","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.devcel.2014.12.024","article-title":"Hoxa2 selectively enhances Meis binding to change a branchial arch ground state","volume":"32","author":"Amin","year":"2015","journal-title":"Dev. Cell"},{"key":"2021042608362817000_DEV133736C4","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1101\/gad.1207204","article-title":"Hoxb1 functions in both motoneurons and in tissues of the periphery to establish and maintain the proper neuronal circuitry","volume":"18","author":"Arenkiel","year":"2004","journal-title":"Genes Dev."},{"key":"2021042608362817000_DEV133736C5","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.ejmg.2014.05.003","article-title":"The genetics of auricular development and malformation: new findings in model systems driving future directions for microtia research","volume":"57","author":"Cox","year":"2014","journal-title":"Eur. J. Med. Genet."},{"key":"2021042608362817000_DEV133736C6","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1111\/j.1469-7580.2011.01375.x","article-title":"The role of masticatory muscles in the continuous loading of the mandible","volume":"218","author":"de Jong","year":"2011","journal-title":"J. Anat."},{"key":"2021042608362817000_DEV133736C7","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/0896-6273(88)90194-8","article-title":"Spatial regulation of axonal glycoprotein expression on subsets of embryonic spinal neurons","volume":"1","author":"Dodd","year":"1988","journal-title":"Neuron"},{"key":"2021042608362817000_DEV133736C8","doi-asserted-by":"publisher","first-page":"3990","DOI":"10.1093\/nar\/gkr1240","article-title":"Genome-wide occupancy links Hoxa2 to Wnt-beta-catenin signaling in mouse embryonic development","volume":"40","author":"Donaldson","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2021042608362817000_DEV133736C9","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1016\/0092-8674(93)90619-2","article-title":"Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest","volume":"75","author":"Gendron-Maguire","year":"1993","journal-title":"Cell"},{"key":"2021042608362817000_DEV133736C10","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1167\/iovs.14-15861","article-title":"Abrogation of HMX1 function causes rare oculoauricular syndrome associated with congenital cataract, anterior segment dysgenesis, and retinal dystrophy","volume":"56","author":"Gillespie","year":"2015","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2021042608362817000_DEV133736C11","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1016\/j.devcel.2015.07.003","article-title":"A cranial mesoderm origin for esophagus striated muscle","volume":"34","author":"Gopalakrishnan","year":"2015","journal-title":"Dev. Cell"},{"key":"2021042608362817000_DEV133736C12","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1590\/S1677-32252013000300010","article-title":"Effects of masticatory hypofunction on mandibular morphology, mineral density and basal bone area","volume":"12","author":"Guerreiro","year":"2013","journal-title":"Braz. J. Oral Sci."},{"key":"2021042608362817000_DEV133736C13","doi-asserted-by":"publisher","first-page":"e77841","DOI":"10.1371\/journal.pone.0077841","article-title":"A non-coding genomic duplication at the HMX1 locus is associated with crop ears in highland cattle","volume":"8","author":"Koch","year":"2013","journal-title":"PLoS ONE"},{"key":"2021042608362817000_DEV133736C14","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1538\/expanim.59.147","article-title":"Genetic analyses of fancy rat-derived mutations","volume":"59","author":"Kuramoto","year":"2010","journal-title":"Exp. Anim."},{"key":"2021042608362817000_DEV133736C15","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1242\/dev.017624","article-title":"Six2 functions redundantly immediately downstream of Hoxa2","volume":"135","author":"Kutejova","year":"2008","journal-title":"Development"},{"key":"2021042608362817000_DEV133736C16","doi-asserted-by":"publisher","DOI":"10.1117\/12.935640","article-title":"Drishti: a volume exploration and presentation tool","author":"Limaye","year":"2012"},{"key":"2021042608362817000_DEV133736C37","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/ajmg.a.34352","article-title":"Microtia: epidemiology and genetics","volume":"158A","author":"Luquetti","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042608362817000_DEV133736C38","doi-asserted-by":"publisher","first-page":"4386","DOI":"10.1242\/dev.098046","article-title":"Mouse Hoxa2 mutations provide a model for microtia and auricle duplication","volume":"140","author":"Minoux","year":"2013","journal-title":"Development"},{"key":"2021042608362817000_DEV133736C17","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/1471-213X-9-27","article-title":"Mouse H6 Homeobox\u00a01 (Hmx1) mutations cause cranial abnormalities and reduced body mass","volume":"9","author":"Munroe","year":"2009","journal-title":"BMC Dev. Biol."},{"key":"2021042608362817000_DEV133736C18","volume-title":"Manipulating the Mouse Embryo: A Laboratory Manual","author":"Nagy","year":"2003"},{"key":"2021042608362817000_DEV133736C19","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1242\/dev.007989","article-title":"The contribution of Islet1-expressing splanchnic mesoderm cells to distinct branchiomeric muscles reveals significant heterogeneity in head muscle development","volume":"135","author":"Nathan","year":"2008","journal-title":"Development"},{"key":"2021042608362817000_DEV133736C20","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1242\/dmm.009910","article-title":"Deletion of a conserved regulatory element required for Hmx1 expression in craniofacial mesenchyme in the dumbo rat: a newly identified cause of congenital ear malformation","volume":"5","author":"Quina","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"2021042608362817000_DEV133736C21","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.ydbio.2012.02.022","article-title":"Hmx1 is required for the normal development of somatosensory neurons in the geniculate ganglion","volume":"365","author":"Quina","year":"2012","journal-title":"Dev. Biol."},{"key":"2021042608362817000_DEV133736C22","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1016\/j.archoralbio.2007.04.014","article-title":"Changes in growth and morphology of the condyle following mandibular distraction in minipigs: overloading or underloading?","volume":"52","author":"Rafferty","year":"2007","journal-title":"Arch. Oral Biol."},{"key":"2021042608362817000_DEV133736C23","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1016\/0092-8674(93)90620-6","article-title":"A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene","volume":"7","author":"Rijli","year":"1993","journal-title":"Cell"},{"key":"2021042608362817000_DEV133736C24","doi-asserted-by":"publisher","first-page":"3065","DOI":"10.1242\/dev.002501","article-title":"Cranial neural crest cells regulate head muscle patterning and differentiation during vertebrate embryogenesis","volume":"134","author":"Rinon","year":"2007","journal-title":"Development"},{"key":"2021042608362817000_DEV133736C25","doi-asserted-by":"publisher","first-page":"2364","DOI":"10.1109\/embc.2013.6610013","article-title":"A new tool for quantifying and characterizing asymmetry in bilaterally paired structures","volume":"2013","author":"Rolfe","year":"2013","journal-title":"Conf. Proc. IEEE Eng. Med. Biol. Soc."},{"key":"2021042608362817000_DEV133736C26","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1186\/s12868-015-0176-0","article-title":"Shox2 is required for the proper development of the facial motor nucleus and the establishment of the facial nerves","volume":"16","author":"Rosin","year":"2015","journal-title":"BMC Neurosci."},{"key":"2021042608362817000_DEV133736C27","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1016\/j.ajhg.2008.03.007","article-title":"Mutation in the human homeobox gene NKX5-3 causes an oculo-auricular syndrome","volume":"82","author":"Schorderet","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"2021042608362817000_DEV133736C28","doi-asserted-by":"crossref","first-page":"3543","DOI":"10.1242\/dev.128.18.3543","article-title":"Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation","volume":"128","author":"Selleri","year":"2001","journal-title":"Development"},{"key":"2021042608362817000_DEV133736C29","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3389\/fphys.2014.00007","article-title":"Genetic evidence for conserved non-coding element function across species\u2013the ears have it","volume":"5","author":"Turner","year":"2014","journal-title":"Front. Physiol."},{"key":"2021042608362817000_DEV133736C30","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.devcel.2006.06.016","article-title":"Reversal of Hox1 gene subfunctionalization in the mouse","volume":"11","author":"Tvrdik","year":"2006","journal-title":"Dev. Cell"},{"key":"2021042608362817000_DEV133736C31","doi-asserted-by":"publisher","first-page":"114","DOI":"10.3109\/13816810.2011.562955","article-title":"Retinal dystrophy in the oculo-auricular syndrome due to HMX1 mutation","volume":"32","author":"Vaclavik","year":"2011","journal-title":"Ophthal. Genet."},{"key":"2021042608362817000_DEV133736C32","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.ydbio.2010.11.031","article-title":"Shox2 function couples neural, muscular and skeletal development in the proximal forelimb","volume":"350","author":"Vickerman","year":"2011","journal-title":"Dev. Biol."},{"key":"2021042608362817000_DEV133736C33","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1242\/dev.125.4.621","article-title":"Inner ear and maternal reproductive defects in mice lacking the Hmx3 homeobox gene","volume":"125","author":"Wang","year":"1998","journal-title":"Development"},{"key":"2021042608362817000_DEV133736C36","doi-asserted-by":"publisher","first-page":"3435","DOI":"10.1182\/blood-2010-04-279497","article-title":"Vascular remodeling of the vitelline artery initiates extravascular emergence of hematopoietic clusters","volume":"116","author":"Zovein","year":"2010","journal-title":"Blood"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.133736","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/143\/14\/2582\/1843656\/dev133736.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.133736\/2052053\/dev_133736v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.133736\/2052053\/dev_133736v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T17:10:00Z","timestamp":1621357800000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.133736\/263969\/A-distal-594bp-ECR-specifies-Hmx1-expression-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,1]]},"references-count":36,"URL":"https:\/\/doi.org\/10.1242\/dev.133736","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2016,1,1]]},"article-number":"dev.133736"}}