{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T15:31:15Z","timestamp":1780587075065,"version":"3.54.1"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2016,12,27]],"date-time":"2016-12-27T00:00:00Z","timestamp":1482796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE020843"],"award-info":[{"award-number":["R01DE020843"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE019527"],"award-info":[{"award-number":["R01DE019527"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR057235"],"award-info":[{"award-number":["AR057235"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK052574"],"award-info":[{"award-number":["DK052574"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Chiled Health and Human Development","award":["R01HD049808"],"award-info":[{"award-number":["R01HD049808"]}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"DOI":"10.1371\/journal.pgen.1006510","type":"journal-article","created":{"date-parts":[[2017,1,9]],"date-time":"2017-01-09T19:59:42Z","timestamp":1483991982000},"page":"e1006510","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":23,"title":["Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2\/Limbin Mutant Mice"],"prefix":"10.1371","volume":"12","author":[{"given":"Honghao","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Kamiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehito","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruko","family":"Takeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2001-3450","authenticated-orcid":true,"given":"Sudha","family":"Rajderkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manas K.","family":"Ray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Mochida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2323-8313","authenticated-orcid":true,"given":"Benjamin","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Lefebvre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene H.","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-7629","authenticated-orcid":true,"given":"David M.","family":"Ornitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Kunieda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Mishina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2016,12,27]]},"reference":[{"key":"ref1","first-page":"306","article-title":"Dwarfism in the Amish I. The Ellis-Van Creveld Syndrome","volume":"115","author":"VA McKusick","year":"1964","journal-title":"Bull Johns Hopkins Hosp"},{"issue":"3","key":"ref2","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/73508","article-title":"Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis","volume":"24","author":"VL Ruiz-Perez","year":"2000","journal-title":"Nat Genet"},{"issue":"3","key":"ref3","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1086\/368063","article-title":"Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome","volume":"72","author":"VL Ruiz-Perez","year":"2003","journal-title":"Am J Hum Genet"},{"issue":"16","key":"ref4","doi-asserted-by":"crossref","first-page":"10549","DOI":"10.1073\/pnas.152337899","article-title":"Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism","volume":"99","author":"H Takeda","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"ref5","doi-asserted-by":"crossref","first-page":"e94861","DOI":"10.1371\/journal.pone.0094861","article-title":"Deletion in the EVC2 gene causes chondrodysplastic dwarfism in Tyrolean Grey cattle","volume":"9","author":"L Murgiano","year":"2014","journal-title":"PLoS One"},{"issue":"6937","key":"ref6","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature01657","article-title":"Developmental regulation of the growth plate","volume":"423","author":"HM Kronenberg","year":"2003","journal-title":"Nature"},{"issue":"1","key":"ref7","doi-asserted-by":"crossref","first-page":"a008334","DOI":"10.1101\/cshperspect.a008334","article-title":"Development of the endochondral skeleton","volume":"5","author":"F Long","year":"2013","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"12","key":"ref8","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1101\/gad.990702","article-title":"FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease","volume":"16","author":"DM Ornitz","year":"2002","journal-title":"Genes Dev"},{"issue":"14","key":"ref9","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1101\/gad.266551.115","article-title":"Fibroblast growth factor signaling in skeletal development and disease","volume":"29","author":"DM Ornitz","year":"2015","journal-title":"Genes Dev"},{"issue":"6622","key":"ref10","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/386288a0","article-title":"Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism","volume":"386","author":"WC Su","year":"1997","journal-title":"Nature"},{"issue":"11","key":"ref11","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1101\/gad.13.11.1361","article-title":"FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway","volume":"13","author":"M Sahni","year":"1999","journal-title":"Genes Dev"},{"issue":"3","key":"ref12","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1101\/gad.1179104","article-title":"Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype","volume":"18","author":"S Murakami","year":"2004","journal-title":"Genes Dev"},{"issue":"16","key":"ref13","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1101\/gad.13.16.2072","article-title":"Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation","volume":"13","author":"B St-Jacques","year":"1999","journal-title":"Genes Dev"},{"issue":"5275","key":"ref14","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1126\/science.273.5275.613","article-title":"Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein","volume":"273","author":"A Vortkamp","year":"1996","journal-title":"Science"},{"issue":"10","key":"ref15","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1242\/dev.131722","article-title":"FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth","volume":"143","author":"K Karuppaiah","year":"2016","journal-title":"Development"},{"issue":"5","key":"ref16","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nrg2774","article-title":"The primary cilium: a signalling centre during vertebrate development","volume":"11","author":"SC Goetz","year":"2010","journal-title":"Nat Rev Genet"},{"issue":"7061","key":"ref17","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/nature04117","article-title":"Vertebrate Smoothened functions at the primary cilium","volume":"437","author":"KC Corbit","year":"2005","journal-title":"Nature"},{"issue":"51","key":"ref18","doi-asserted-by":"crossref","first-page":"21666","DOI":"10.1073\/pnas.0912180106","article-title":"Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus","volume":"106","author":"J Kim","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"ref19","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1101\/gad.1902910","article-title":"The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins","volume":"24","author":"EW Humke","year":"2010","journal-title":"Genes Dev"},{"issue":"2","key":"ref20","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1083\/jcb.201004108","article-title":"A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes","volume":"191","author":"H Tukachinsky","year":"2010","journal-title":"J Cell Biol"},{"issue":"4","key":"ref21","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.devcel.2012.07.004","article-title":"A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia","volume":"23","author":"KV Dorn","year":"2012","journal-title":"Dev Cell"},{"issue":"11","key":"ref22","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1038\/cr.2012.134","article-title":"Smoothened transduces Hedgehog signal by forming a complex with Evc\/Evc2","volume":"22","author":"C Yang","year":"2012","journal-title":"Cell Res"},{"issue":"1","key":"ref23","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/hmg\/dds409","article-title":"The ciliary Evc\/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu\/Gli3 dissociation and Gli3 trafficking in primary cilia","volume":"22","author":"JA Caparros-Martin","year":"2013","journal-title":"Hum Mol Genet"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1741-7007-9-14","article-title":"Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus","volume":"9","author":"HJ Blair","year":"2011","journal-title":"BMC Biol"},{"issue":"5","key":"ref25","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.devcel.2014.01.021","article-title":"EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia","volume":"28","author":"GV Pusapati","year":"2014","journal-title":"Dev Cell"},{"issue":"16","key":"ref26","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1242\/dev.007542","article-title":"Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia","volume":"134","author":"VL Ruiz-Perez","year":"2007","journal-title":"Development"},{"issue":"9","key":"ref27","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1002\/dvg.22879","article-title":"Generation of Evc2\/Limbin global and conditional KO mice and its roles during mineralized tissue formation","volume":"53","author":"H Zhang","year":"2015","journal-title":"genesis"},{"issue":"6599","key":"ref28","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/383407a0","article-title":"Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function","volume":"383","author":"C Chiang","year":"1996","journal-title":"Nature"},{"issue":"9","key":"ref29","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/bdra.20295","article-title":"Holoprosencephaly: clinical, anatomic, and molecular dimensions","volume":"76","author":"MM Cohen Jr","year":"2006","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"issue":"2","key":"ref30","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1006\/dbio.2001.0346","article-title":"Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function","volume":"236","author":"C Chiang","year":"2001","journal-title":"Dev Biol"},{"issue":"15","key":"ref31","doi-asserted-by":"crossref","first-page":"6382","DOI":"10.1073\/pnas.0608449104","article-title":"Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone","volume":"104","author":"Y Maeda","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"ref32","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00439-006-0237-7","article-title":"Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients","volume":"120","author":"SW Tompson","year":"2007","journal-title":"Hum Genet"},{"issue":"19","key":"ref33","doi-asserted-by":"crossref","first-page":"3867","DOI":"10.1242\/dev.128.19.3867","article-title":"Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains","volume":"128","author":"Q Wang","year":"2001","journal-title":"Development"},{"issue":"2","key":"ref34","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/ng0696-233","article-title":"Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia","volume":"13","author":"MC Naski","year":"1996","journal-title":"Nat Genet"},{"issue":"2","key":"ref35","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1006\/dbio.1993.1040","article-title":"Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis","volume":"155","author":"K Peters","year":"1993","journal-title":"Dev Biol"},{"issue":"1","key":"ref36","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1242\/dev.114.1.233","article-title":"Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse","volume":"114","author":"KG Peters","year":"1992","journal-title":"Development"},{"issue":"43","key":"ref37","doi-asserted-by":"crossref","first-page":"30934","DOI":"10.1074\/jbc.274.43.30934","article-title":"Fibroblast growth factor receptor 3 gene transcription is suppressed by cyclic adenosine 3&apos;,5&apos;-monophosphate. Identification of a chondrocytic regulatory element","volume":"274","author":"DG McEwen","year":"1999","journal-title":"J Biol Chem"},{"key":"ref38","first-page":"243","article-title":"PTH and PTHrP: Similar Structures but Different Functions","volume":"14","author":"KD Schluter","year":"1999","journal-title":"News Physiol Sci"},{"issue":"7","key":"ref39","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1101\/gad.965702","article-title":"FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis","volume":"16","author":"N Ohbayashi","year":"2002","journal-title":"Genes Dev"},{"issue":"7","key":"ref40","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1101\/gad.965602","article-title":"Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18","volume":"16","author":"Z Liu","year":"2002","journal-title":"Genes Dev"},{"issue":"1","key":"ref41","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ydbio.2016.01.008","article-title":"A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development","volume":"411","author":"IH Hung","year":"2016","journal-title":"Dev Biol"},{"issue":"2","key":"ref42","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.ydbio.2007.04.048","article-title":"FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod","volume":"307","author":"IH Hung","year":"2007","journal-title":"Dev Biol"},{"issue":"3","key":"ref43","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.devcel.2011.12.024","article-title":"Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes","volume":"22","author":"P Dy","year":"2012","journal-title":"Dev Cell"},{"issue":"13","key":"ref44","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1242\/dev.00491","article-title":"Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth","volume":"130","author":"K Yu","year":"2003","journal-title":"Development"},{"issue":"1","key":"ref45","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.ydbio.2007.02.003","article-title":"Development of the post-natal growth plate requires intraflagellar transport proteins","volume":"305","author":"B Song","year":"2007","journal-title":"Dev Biol"},{"issue":"7238","key":"ref46","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nature07753","article-title":"FGF signalling during embryo development regulates cilia length in diverse epithelia","volume":"458","author":"JM Neugebauer","year":"2009","journal-title":"Nature"},{"issue":"7","key":"ref47","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1242\/dev.118802","article-title":"Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis","volume":"142","author":"S Hayano","year":"2015","journal-title":"Development"},{"issue":"12","key":"ref48","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1084\/jem.20011700","article-title":"Mesenchymal stem cells in perichondrium express activated leukocyte cell adhesion molecule and participate in bone marrow formation","volume":"195","author":"F Arai","year":"2002","journal-title":"J Exp Med"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-60327-292-6_1","article-title":"In situ hybridization methods for mouse whole mounts and tissue sections with and without additional beta-galactosidase staining","volume":"1092","author":"Y Komatsu","year":"2014","journal-title":"Methods Mol Biol"}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pgen.1006510","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T02:12:23Z","timestamp":1658369543000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1006510"}},"subtitle":[],"editor":[{"given":"Fanxin","family":"Long","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2016,12,27]]},"references-count":49,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2016,12,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1006510","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,27]]}}}