{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:11:08Z","timestamp":1791259868647,"version":"4.1.0"},"reference-count":38,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2014M3A9D5A01073865"],"award-info":[{"award-number":["2014M3A9D5A01073865"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Defects in the middle ear ossicles - malleus, incus, and stapes - can lead to conductive hearing loss. During development, neural crest cells (NCCs) migrate from the dorsal hindbrain to specific locations in pharyngeal arch (PA) 1 and 2, to form the malleus-incus and stapes, respectively. It is unclear how migratory NCCs reach their proper destination in PA and initiate mesenchymal condensation to form specific ossicles. We show that secreted molecules sonic hedgehog (SHH) and bone morphogenetic protein 4 (BMP4) emanating from the pharyngeal endoderm are important in instructing regional-specific NCC condensation to form malleus-incus and stapes, respectively. Tissue-specific knockout of Shh in the pharyngeal endoderm or Smoothened (a transducer of SHH signaling) in NCCs causes the loss of malleus-incus condensation in PA1 but only affects the maintenance of stapes condensation in PA2. By contrast, knockout of Bmp4 in the pharyngeal endoderm or Smad4 (a transducer of TGF-\u03b2\/BMP signaling) in the NCCs disrupts NCC migration into the stapes region in PA2, affecting the stapes formation. These results indicate that regional-specific endodermal signals direct formation of specific middle ear ossicles.<\/jats:p>","DOI":"10.1242\/dev.167965","type":"journal-article","created":{"date-parts":[[2019,1,10]],"date-time":"2019-01-10T16:26:05Z","timestamp":1547137565000},"source":"Crossref","is-referenced-by-count":17,"title":["Regional-specific endodermal signals direct neural crest cells to form the three middle ear ossicles"],"prefix":"10.1242","author":[{"given":"Harinarayana","family":"Ankamreddy","sequence":"first","affiliation":[{"name":"Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea"},{"name":"BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyehyun","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Yoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea"},{"name":"BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0298-9831","authenticated-orcid":false,"given":"Xiao","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eui-Sic","family":"Cho","sequence":"additional","affiliation":[{"name":"Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Chonbuk National University School of Dentistry, Jeonju, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Un-Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea"},{"name":"School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1958-1872","authenticated-orcid":false,"given":"Jinwoong","family":"Bok","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea"},{"name":"BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea"},{"name":"Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,1,1]]},"reference":[{"key":"2021042513273012100_DEV167965C1","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1242\/dev.129.19.4613","article-title":"Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse","volume":"129","author":"Abu-Issa","year":"2002","journal-title":"Development"},{"key":"2021042513273012100_DEV167965C2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0092-8674(01)00191-X","article-title":"The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration","volume":"104","author":"Adams","year":"2001","journal-title":"Cell"},{"key":"2021042513273012100_DEV167965C3","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1016\/S0960-9822(00)80052-4","article-title":"Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death","volume":"9","author":"Ahlgren","year":"1999","journal-title":"Curr. Biol."},{"key":"2021042513273012100_DEV167965C4","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/joa.12344","article-title":"The development of the mammalian outer and middle ear","volume":"228","author":"Anthwal","year":"2016","journal-title":"J. Anat."},{"key":"2021042513273012100_DEV167965C5","doi-asserted-by":"publisher","first-page":"e216","DOI":"10.1371\/journal.pgen.0020216","article-title":"Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis","volume":"2","author":"Bandyopadhyay","year":"2006","journal-title":"PLoS Genet."},{"key":"2021042513273012100_DEV167965C6","doi-asserted-by":"publisher","first-page":"a008326","DOI":"10.1101\/cshperspect.a008326","article-title":"Signals and switches in Mammalian neural crest cell differentiation","volume":"5","author":"Bhatt","year":"2013","journal-title":"Cold Spring Harb. Perspect Biol."},{"key":"2021042513273012100_DEV167965C7","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1002\/dvdy.24256","article-title":"Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation","volume":"244","author":"Billmyre","year":"2015","journal-title":"Dev. Dyn."},{"key":"2021042513273012100_DEV167965C8","doi-asserted-by":"publisher","first-page":"13869","DOI":"10.1073\/pnas.1222341110","article-title":"Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells","volume":"110","author":"Bok","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042513273012100_DEV167965C9","doi-asserted-by":"publisher","first-page":"11607","DOI":"10.1073\/pnas.0604751103","article-title":"An early role for sonic hedgehog from foregut endoderm in jaw development: ensuring neural crest cell survival","volume":"103","author":"Brito","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042513273012100_DEV167965C10","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1242\/dev.127.8.1671","article-title":"Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis","volume":"127","author":"Chai","year":"2000","journal-title":"Development"},{"key":"2021042513273012100_DEV167965C11","doi-asserted-by":"publisher","first-page":"e1000050","DOI":"10.1371\/journal.pgen.1000050","article-title":"Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements","volume":"4","author":"Chang","year":"2008","journal-title":"PLoS Genet."},{"key":"2021042513273012100_DEV167965C12","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.2741\/3813","article-title":"Can you hear me now? Understanding vertebrate middle ear development","volume":"16","author":"Chapman","year":"2011","journal-title":"Front. Biosci."},{"key":"2021042513273012100_DEV167965C13","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1242\/dev.129.4.1061","article-title":"Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head","volume":"129","author":"Couly","year":"2002","journal-title":"Development"},{"key":"2021042513273012100_DEV167965C14","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/0092-8674(93)90627-3","article-title":"Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity","volume":"75","author":"Echelard","year":"1993","journal-title":"Cell"},{"key":"2021042513273012100_DEV167965C15","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1242\/dev.126573","article-title":"Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations","volume":"143","author":"Escot","year":"2016","journal-title":"Development"},{"key":"2021042513273012100_DEV167965C16","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1101\/gad.10.3.301","article-title":"Conservation of the hedgehog\/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog","volume":"10","author":"Goodrich","year":"1996","journal-title":"Genes Dev."},{"key":"2021042513273012100_DEV167965C17","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1006\/dbio.2000.9732","article-title":"Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures","volume":"222","author":"H\u00e9bert","year":"2000","journal-title":"Dev. Biol."},{"key":"2021042513273012100_DEV167965C18","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1101\/gad.1190304","article-title":"Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia","volume":"18","author":"Jeong","year":"2004","journal-title":"Genes Dev."},{"key":"2021042513273012100_DEV167965C19","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1242\/dev.127.5.1095","article-title":"BMP signaling is essential for development of skeletogenic and neurogenic cranial neural crest","volume":"127","author":"Kanzler","year":"2000","journal-title":"Development"},{"key":"2021042513273012100_DEV167965C20","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.ydbio.2007.09.050","article-title":"Smad4 is required to regulate the fate of cranial neural crest cells","volume":"312","author":"Ko","year":"2007","journal-title":"Dev. Biol."},{"key":"2021042513273012100_DEV167965C21","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1002\/dvdy.23768","article-title":"Fibroblast growth factor and bone morphogenetic protein signaling are required for specifying prechondrogenic identity in neural crest-derived mesenchyme and initiating the chondrogenic program","volume":"241","author":"Kumar","year":"2012","journal-title":"Dev. Dyn."},{"key":"2021042513273012100_DEV167965C22","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1242\/dev.040048","article-title":"Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development","volume":"137","author":"Minoux","year":"2010","journal-title":"Development"},{"key":"2021042513273012100_DEV167965C23","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.ydbio.2004.10.027","article-title":"Differential expression of Sonic hedgehog along the anterior-posterior axis regulates patterning of pharyngeal pouch endoderm and pharyngeal endoderm-derived organs","volume":"278","author":"Moore-Scott","year":"2005","journal-title":"Dev. Biol."},{"key":"2021042513273012100_DEV167965C24","doi-asserted-by":"publisher","first-page":"3327","DOI":"10.1523\/JNEUROSCI.18-09-03327.1998","article-title":"Development of the mouse inner ear and origin of its sensory organs","volume":"18","author":"Morsli","year":"1998","journal-title":"J. Neurosci."},{"key":"2021042513273012100_DEV167965C25","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.ydbio.2009.06.031","article-title":"A role for chemokine signaling in neural crest cell migration and craniofacial development","volume":"333","author":"Olesnicky Killian","year":"2009","journal-title":"Dev. Biol."},{"key":"2021042513273012100_DEV167965C26","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1002\/ar.23457","article-title":"Morphogenesis of the middle ear ossicles and spatial relationships with the external and inner ears during the embryonic period","volume":"299","author":"Ozeki-Satoh","year":"2016","journal-title":"Anat. Rec."},{"key":"2021042513273012100_DEV167965C27","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1159\/000380940","article-title":"Congenital middle ear anomalies: anatomical and functional results of surgery","volume":"20","author":"Quesnel","year":"2015","journal-title":"Audiol. Neurootol."},{"key":"2021042513273012100_DEV167965C28","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1126\/science.1222369","article-title":"The dorsal aorta initiates a molecular cascade that instructs sympatho-adrenal specification","volume":"336","author":"Saito","year":"2012","journal-title":"Science"},{"key":"2021042513273012100_DEV167965C29","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1083\/jcb.114.6.1307","article-title":"Alternatively spliced type II procollagen mRNAs define distinct populations of cells during vertebral development: differential expression of the amino-propeptide","volume":"114","author":"Sandell","year":"1991","journal-title":"J. Cell Biol."},{"key":"2021042513273012100_DEV167965C30","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1002\/(SICI)1097-0177(200004)217:4&lt;401::AID-DVDY7&gt;3.0.CO;2-D","article-title":"Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2","volume":"217","author":"Semba","year":"2000","journal-title":"Dev. Dyn."},{"key":"2021042513273012100_DEV167965C31","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/5007","article-title":"Generalized lacZ expression with the ROSA26 Cre reporter strain","volume":"21","author":"Soriano","year":"1999","journal-title":"Nat. Genet."},{"key":"2021042513273012100_DEV167965C32","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.ydbio.2012.08.003","article-title":"Ectodermal-derived Endothelin1 is required for patterning the distal and intermediate domains of the mouse mandibular arch","volume":"371","author":"Tavares","year":"2012","journal-title":"Dev. Biol."},{"key":"2021042513273012100_DEV167965C33","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.1359\/JBMR.040706","article-title":"Targeted expression of SHH affects chondrocyte differentiation, growth plate organization, and Sox9 expression","volume":"19","author":"Tavella","year":"2004","journal-title":"J. Bone Miner. Res."},{"key":"2021042513273012100_DEV167965C34","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.matbio.2006.07.005","article-title":"Forced chondrocyte expression of sonic hedgehog impairs joint formation affecting proliferation and apoptosis","volume":"25","author":"Tavella","year":"2006","journal-title":"Matrix Biol."},{"key":"2021042513273012100_DEV167965C35","doi-asserted-by":"publisher","first-page":"3136","DOI":"10.1101\/gad.13.23.3136","article-title":"Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch","volume":"13","author":"Trumpp","year":"1999","journal-title":"Genes Dev."},{"key":"2021042513273012100_DEV167965C36","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1242\/dev.01017","article-title":"Bapx1 regulates patterning in the middle ear: altered regulatory role in the transition from the proximal jaw during vertebrate evolution","volume":"131","author":"Tucker","year":"2004","journal-title":"Development"},{"key":"2021042513273012100_DEV167965C37","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/ng0195-15","article-title":"The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos","volume":"9","author":"Wright","year":"1995","journal-title":"Nat. Genet."},{"key":"2021042513273012100_DEV167965C38","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1002\/dvdy.23788","article-title":"Induction of the chick columella and its integration with the inner ear","volume":"241","author":"Zou","year":"2012","journal-title":"Dev. Dyn."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.167965","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.167965\/1871283\/dev167965.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.167965\/2054652\/dev_167965v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.167965\/2054652\/dev_167965v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T16:45:21Z","timestamp":1621356321000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.167965\/264600\/Regional-specific-endodermal-signals-direct-neural"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,1]]},"references-count":38,"URL":"https:\/\/doi.org\/10.1242\/dev.167965","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2019,1,1]]},"article-number":"dev.167965"}}