{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T19:28:36Z","timestamp":1791660516888,"version":"4.3.4"},"reference-count":37,"publisher":"The Company of Biologists","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,1]]},"abstract":"<jats:p>Disrupted ERK1\/2 signaling is associated with several developmental syndromes in humans. To understand the function of Erk2 in the postmigratory neural crest populating the craniofacial region, we studied two mouse models: Wnt1-Cre;Erk2fl\/fl and Osr2-Cre;Erk2fl\/fl. Wnt1-Cre;Erk2fl\/fl mice exhibited cleft palate, malformed tongue, micrognathia and mandibular asymmetry. Cleft palate in these mice was associated with delay\/failure of palatal shelf elevation, caused by tongue malposition and micrognathia. Osr2-Cre;Erk2fl\/fl mice, in which the Erk2 deletion is restricted to the palatal mesenchyme, did not display cleft palate, suggesting that palatal clefting in Wnt1-Cre;Erk2fl\/fl mice is a secondary defect. Tongues in Wnt1-Cre;Erk2fl\/fl mice exhibited microglossia, malposition, disruption of the muscle patterning, and compromised tendon development. The tongue phenotype was extensively rescued after culture in isolation, indicating that it might also be a secondary defect. The primary malformations in Wnt1-Cre;Erk2fl\/fl mice, micrognathia and mandibular asymmetry, are linked to an early osteogenic differentiation defect. Collectively, our study demonstrates that mutation of Erk2 in neural crest derivatives phenocopies the human Pierre Robin sequence and highlights the interconnection of palate, tongue, and mandible development. Because the ERK pathway serves as a crucial point of convergence for multiple signaling pathways, our study will facilitate a better understanding of the molecular regulatory mechanisms of craniofacial development.<\/jats:p>","DOI":"10.1242\/dev.125328","type":"journal-article","created":{"date-parts":[[2015,9,23]],"date-time":"2015-09-23T03:38:24Z","timestamp":1442979504000},"source":"Crossref","is-referenced-by-count":33,"title":["Disruption of the ERK\/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence"],"prefix":"10.1242","author":[{"given":"Carolina","family":"Parada","sequence":"first","affiliation":[{"name":"Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Han","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Grimaldi","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Sarri\u00f3n","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shery S.","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Pelikan","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro A.","family":"Sanchez-Lara","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA"},{"name":"Department of Pathology & Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA"},{"name":"Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Chai","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608130722200_DEV125328C1","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1002\/humu.20748","article-title":"The RAS\/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders","volume":"29","author":"Aoki","year":"2008","journal-title":"Hum. Mutat."},{"key":"2021042608130722200_DEV125328C2","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1093\/hmg\/ddp543","article-title":"Prdm16 is required for normal palatogenesis in mice","volume":"19","author":"Bjork","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2021042608130722200_DEV125328C3","first-page":"93","article-title":"The mechanical role of the cranial base in palatal shelf movement: an experimental re-examination","volume":"48","author":"Brinkley","year":"1978","journal-title":"J. Embryol. Exp. Morphol."},{"key":"2021042608130722200_DEV125328C4","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1242\/dev.067082","article-title":"Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development","volume":"139","author":"Bush","year":"2012","journal-title":"Development"},{"key":"2021042608130722200_DEV125328C5","doi-asserted-by":"publisher","first-page":"2353","DOI":"10.1002\/dvdy.20833","article-title":"Recent advances in craniofacial morphogenesis","volume":"235","author":"Chai","year":"2006","journal-title":"Dev. Dyn."},{"key":"2021042608130722200_DEV125328C6","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":"2021042608130722200_DEV125328C8","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/jbmr.2409","article-title":"ERK1 and ERK2 regulate chondrocyte terminal differentiation during endochondral bone formation","volume":"30","author":"Chen","year":"2014","journal-title":"J. Bone Miner. Res."},{"key":"2021042608130722200_DEV125328C9","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.1242\/dev.00669","article-title":"Spatial and temporal patterns of ERK signaling during mouse embryogenesis","volume":"130","author":"Corson","year":"2003","journal-title":"Development"},{"key":"2021042608130722200_DEV125328C10","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1098\/rstb.1993.0074","article-title":"Isolation and characterization of SRF accessory proteins","volume":"340","author":"Dalton","year":"1993","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"2021042608130722200_DEV125328C11","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/BF00428098","article-title":"The mechanism of palatal shelf elevation and the pathogenesis of cleft palate","volume":"375","author":"Ferguson","year":"1977","journal-title":"Virchows Arch. A Pathol. Anat. Histol."},{"issue":"Suppl","key":"2021042608130722200_DEV125328C12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1242\/dev.103.Supplement.41","article-title":"Palate development","volume":"103","author":"Ferguson","year":"1988","journal-title":"Development"},{"key":"2021042608130722200_DEV125328C13","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1083\/jcb.200610046","article-title":"Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development","volume":"176","author":"Ge","year":"2007","journal-title":"J. Cell Biol."},{"key":"2021042608130722200_DEV125328C15","doi-asserted-by":"publisher","first-page":"3120","DOI":"10.1128\/MCB.00623-14","article-title":"ALK5-mediated transforming growth factor \u03b2 signaling in neural crest cells controls craniofacial muscle development via tissue-tissue interactions","volume":"34","author":"Han","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"2021042608130722200_DEV125328C16","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.ydbio.2010.02.030","article-title":"TGF-beta mediated FGF10 signaling in cranial neural crest cells controls development of myogenic progenitor cells through tissue\u2013tissue interactions during tongue morphogenesis","volume":"341","author":"Hosokawa","year":"2010","journal-title":"Dev. Biol."},{"key":"2021042608130722200_DEV125328C17","doi-asserted-by":"publisher","first-page":"3079","DOI":"10.1002\/dvdy.21714","article-title":"Gli3-deficient mice exhibit cleft palate associated with abnormal tongue development","volume":"237","author":"Huang","year":"2008","journal-title":"Dev. Dyn."},{"key":"2021042608130722200_DEV125328C18","doi-asserted-by":"publisher","first-page":"5269","DOI":"10.1242\/dev.00708","article-title":"Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects","volume":"130","author":"Ito","year":"2003","journal-title":"Development"},{"key":"2021042608130722200_DEV125328C19","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1111\/j.1601-0825.2011.01806.x","article-title":"The mechanism of TGF-\u03b2 signaling during palate development","volume":"17","author":"Iwata","year":"2011","journal-title":"Oral Dis."},{"key":"2021042608130722200_DEV125328C20","doi-asserted-by":"publisher","first-page":"29760","DOI":"10.1074\/jbc.M113.493551","article-title":"Noncanonical transforming growth factor \u03b2 (TGF\u03b2) signaling in cranial neural crest cells causes tongue muscle developmental defects","volume":"288","author":"Iwata","year":"2013","journal-title":"J. Biol. Chem."},{"key":"2021042608130722200_DEV125328C21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s00774-011-0288-2","article-title":"FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation","volume":"30","author":"Kyono","year":"2012","journal-title":"J. Bone Miner. Metab."},{"key":"2021042608130722200_DEV125328C22","doi-asserted-by":"publisher","first-page":"5843","DOI":"10.1128\/MCB.01549-08","article-title":"Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis","volume":"29","author":"Matsushita","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"2021042608130722200_DEV125328C23","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/374356a0","article-title":"Different phenotypes for mice deficient in either activins or activin receptor type II","volume":"374","author":"Matzuk","year":"1995","journal-title":"Nature"},{"key":"2021042608130722200_DEV125328C24","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/sj.ejhg.5200950","article-title":"Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia","volume":"11","author":"Melkoniemi","year":"2003","journal-title":"Eur. J. Hum. Genet."},{"key":"2021042608130722200_DEV125328C26","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1002\/ajmg.a.31658","article-title":"Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome","volume":"143A","author":"Narumi","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042608130722200_DEV125328C27","doi-asserted-by":"publisher","first-page":"17115","DOI":"10.1073\/pnas.0805239105","article-title":"Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development","volume":"105","author":"Newbern","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608130722200_DEV125328C28","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/BF01628309","article-title":"The relationship between Meckel's cartilage and the development of the human fetal mandible","volume":"15","author":"Orliaguet","year":"1993","journal-title":"Surg. Radiol. Anat."},{"key":"2021042608130722200_DEV125328C29","doi-asserted-by":"publisher","first-page":"3482","DOI":"10.1128\/MCB.00615-13","article-title":"CTGF mediates Smad-dependent transforming growth factor \u03b2 signaling to regulate mesenchymal cell proliferation during palate development","volume":"33","author":"Parada","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"2021042608130722200_DEV125328C30","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1210\/er.22.2.153","article-title":"Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions","volume":"22","author":"Pearson","year":"2001","journal-title":"Endocr. Rev."},{"key":"2021042608130722200_DEV125328C31","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1046\/j.1469-7580.2003.00210.x","article-title":"The growth and morphogenesis of the early mouse mandible: a quantitative analysis","volume":"203","author":"Ramaesh","year":"2003","journal-title":"J. Anat."},{"key":"2021042608130722200_DEV125328C32","doi-asserted-by":"publisher","first-page":"222","DOI":"10.4103\/0976-237X.86467","article-title":"Pierre robin sequence and the pediatric dentist","volume":"2","author":"Rangeeth","year":"2011","journal-title":"Contemp. Clin. Dent."},{"key":"2021042608130722200_DEV125328C33","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1136\/jmg.2006.042796","article-title":"The cardiofaciocutaneous syndrome","volume":"43","author":"Roberts","year":"2006","journal-title":"J. Med. Genet."},{"key":"2021042608130722200_DEV125328C34","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1016\/S1357-2725(03)00031-1","article-title":"Ternary complex factors: prime nuclear targets for mitogen-activated protein kinases","volume":"35","author":"Shaw","year":"2003","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2021042608130722200_DEV125328C35","doi-asserted-by":"publisher","first-page":"2067","DOI":"10.1093\/bioinformatics\/bti270","article-title":"Use of within-array replicate spots for assessing differential expression in microarray experiments","volume":"21","author":"Smyth","year":"2005","journal-title":"Bioinformatics"},{"key":"2021042608130722200_DEV125328C36","doi-asserted-by":"publisher","first-page":"10440","DOI":"10.1074\/jbc.M112.432286","article-title":"Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development","volume":"288","author":"Song","year":"2013","journal-title":"J. Biol. Chem."},{"key":"2021042608130722200_DEV125328C37","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/ajmg.c.31374","article-title":"Developmental and genetic perspectives on Pierre Robin sequence","volume":"163","author":"Tan","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2021042608130722200_DEV125328C38","first-page":"75","article-title":"Whole mount in situ hybridization of vertebrate embryos","volume-title":"In Situ Hybridization","author":"Wilkinson","year":"1992"},{"key":"2021042608130722200_DEV125328C39","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1002\/dvdy.20197","article-title":"PDGFR-\u03b1 signaling is critical for tooth cusp and palate morphogenesis","volume":"232","author":"Xu","year":"2005","journal-title":"Dev. Dyn."},{"key":"2021042608130722200_DEV125328C40","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1002\/dvdy.22670","article-title":"Histomorphological study of palatal shelf elevation during murine secondary palate formation","volume":"240","author":"Yu","year":"2011","journal-title":"Dev. Dyn."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/142\/21\/3734\/1839377\/dev125328.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.125328\/2033923\/dev_125328v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.125328\/2033923\/dev_125328v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T20:49:49Z","timestamp":1621370989000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.125328\/256985\/Disruption-of-the-ERK-MAPK-pathway-in-neural-crest"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,1]]},"references-count":37,"URL":"https:\/\/doi.org\/10.1242\/dev.125328","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2015,1,1]]},"article-number":"dev.125328"}}