{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:44:53Z","timestamp":1791121493890,"version":"4.1.0"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2014,1,9]],"date-time":"2014-01-09T00:00:00Z","timestamp":1389225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"DOI":"10.1371\/journal.pgen.1004072","type":"journal-article","created":{"date-parts":[[2014,1,9]],"date-time":"2014-01-09T21:25:39Z","timestamp":1389302739000},"page":"e1004072","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":50,"title":["GATA6 Is a Crucial Regulator of Shh in the Limb Bud"],"prefix":"10.1371","volume":"10","author":[{"given":"Elena","family":"Kozhemyakina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreia","family":"Ionescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Lassar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2014,1,9]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/0092-8674(93)90626-2","article-title":"Sonic hedgehog mediates the polarizing activity of the ZPA","volume":"75","author":"RD Riddle","year":"1993","journal-title":"Cell"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.devcel.2008.01.008","article-title":"Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud","volume":"14","author":"J Zhu","year":"2008","journal-title":"Dev Cell"},{"key":"ref3","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"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nrg2681","article-title":"Vertebrate limb bud development: moving towards integrative analysis of organogenesis","volume":"10","author":"R Zeller","year":"2009","journal-title":"Nat Rev Genet"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1242\/dev.024158","article-title":"Growing models of vertebrate limb development","volume":"136","author":"M Towers","year":"2009","journal-title":"Development"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.devcel.2008.11.010","article-title":"Hedgehog signaling in development and cancer","volume":"15","author":"J Jiang","year":"2008","journal-title":"Dev Cell"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1073\/pnas.0509927103","article-title":"Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing","volume":"103","author":"B Wang","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1128\/MCB.26.9.3365-3377.2006","article-title":"Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation","volume":"26","author":"Y Pan","year":"2006","journal-title":"Mol Cell Biol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"19320","DOI":"10.1074\/jbc.M513203200","article-title":"Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase","volume":"281","author":"N Bhatia","year":"2006","journal-title":"J Biol Chem"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1126\/science.1139740","article-title":"Patched1 regulates hedgehog signaling at the primary cilium","volume":"317","author":"R Rohatgi","year":"2007","journal-title":"Science"},{"key":"ref11","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"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/nature01033","article-title":"Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity","volume":"418","author":"Y Litingtung","year":"2002","journal-title":"Nature"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1126\/science.1075620","article-title":"Progression of vertebrate limb development through SHH-mediated counteraction of GLI3","volume":"298","author":"P te Welscher","year":"2002","journal-title":"Science"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.ydbio.2007.02.029","article-title":"The Shh-independent activator function of the full-length Gli3 protein and its role in vertebrate limb digit patterning","volume":"305","author":"C Wang","year":"2007","journal-title":"Dev Biol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"7548","DOI":"10.1073\/pnas.112212199","article-title":"Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly","volume":"99","author":"LA Lettice","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1093\/hmg\/ddg180","article-title":"A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly","volume":"12","author":"LA Lettice","year":"2003","journal-title":"Hum Mol Genet"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.devcel.2011.12.010","article-title":"Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly","volume":"22","author":"LA Lettice","year":"2012","journal-title":"Dev Cell"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/ajmg.a.31563","article-title":"Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly","volume":"143","author":"CA Gurnett","year":"2007","journal-title":"Am J Med Genet A"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ydbio.2010.08.015","article-title":"Twist1 activity thresholds define multiple functions in limb development","volume":"347","author":"D Krawchuk","year":"2010","journal-title":"Dev Biol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1242\/dev.051789","article-title":"Preaxial polydactyly: interactions among ETV, TWIST1 and HAND2 control anterior-posterior patterning of the limb","volume":"137","author":"Z Zhang","year":"2010","journal-title":"Development"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.1242\/dev.124.20.3999","article-title":"Polydactyly and ectopic ZPA formation in Alx-4 mutant mice","volume":"124","author":"S Qu","year":"1997","journal-title":"Development"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.ydbio.2005.06.017","article-title":"Function and regulation of Alx4 in limb development: complex genetic interactions with Gli3 and Shh","volume":"285","author":"S Kuijper","year":"2005","journal-title":"Dev Biol"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1242\/dev.127.11.2461","article-title":"The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development","volume":"127","author":"J Charite","year":"2000","journal-title":"Development"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1242\/dev.127.10.2133","article-title":"Role of dHAND in the anterior-posterior polarization of the limb bud: implications for the Sonic hedgehog pathway","volume":"127","author":"M Fernandez-Teran","year":"2000","journal-title":"Development"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1242\/jcs.062901","article-title":"Regulation of BMP-dependent chondrogenesis in early limb mesenchyme by TGFbeta signals","volume":"123","author":"K Karamboulas","year":"2010","journal-title":"J Cell Sci"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.ydbio.2007.12.001","article-title":"A role for GATA-6 in vertebrate chondrogenesis","volume":"314","author":"A Alexandrovich","year":"2008","journal-title":"Dev Biol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.semcdb.2004.10.006","article-title":"Coregulation of GATA factors by the Friend of GATA (FOG) family of multitype zinc finger proteins","volume":"16","author":"AB Cantor","year":"2005","journal-title":"Semin Cell Dev Biol"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1242\/dev.023010","article-title":"Crucial role of vHNF1 in vertebrate hepatic specification","volume":"135","author":"L Lokmane","year":"2008","journal-title":"Development"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1006\/dbio.1996.0165","article-title":"GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm","volume":"177","author":"EE Morrisey","year":"1996","journal-title":"Dev Biol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1471-213X-6-19","article-title":"Generation of mice harbouring a conditional loss-of-function allele of Gata6","volume":"6","author":"CP Sodhi","year":"2006","journal-title":"BMC Dev Biol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.1101\/gad.12.22.3579","article-title":"GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo","volume":"12","author":"EE Morrisey","year":"1998","journal-title":"Genes Dev"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1242\/dev.126.4.723","article-title":"The transcription factor GATA6 is essential for early extraembryonic development","volume":"126","author":"M Koutsourakis","year":"1999","journal-title":"Development"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/gene.10092","article-title":"Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer","volume":"33","author":"M Logan","year":"2002","journal-title":"Genesis"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.mod.2008.01.001","article-title":"Polydactyly in the mouse mutant Doublefoot involves altered Gli3 processing and is caused by a large deletion in cis to Indian hedgehog","volume":"125","author":"C Babbs","year":"2008","journal-title":"Mech Dev"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1101\/gad.369106","article-title":"The chicken talpid3 gene encodes a novel protein essential for Hedgehog signaling","volume":"20","author":"MG Davey","year":"2006","journal-title":"Genes Dev"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1006\/dbio.1999.9321","article-title":"Constitutive activation of sonic hedgehog signaling in the chicken mutant talpid(2): Shh-independent outgrowth and polarizing activity","volume":"212","author":"NC Caruccio","year":"1999","journal-title":"Dev Biol"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1242\/dev.125.16.3123","article-title":"Evidence that preaxial polydactyly in the Doublefoot mutant is due to ectopic Indian Hedgehog signaling","volume":"125","author":"Y Yang","year":"1998","journal-title":"Development"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1242\/dev.037507","article-title":"Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb","volume":"136","author":"NC Butterfield","year":"2009","journal-title":"Development"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1093\/nar\/gni051","article-title":"Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction","volume":"33","author":"G Belteki","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1101\/gad.938601","article-title":"Hedgehog signaling in animal development: paradigms and principles","volume":"15","author":"PW Ingham","year":"2001","journal-title":"Genes Dev"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1242\/dev.01115","article-title":"Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh","volume":"131","author":"Y Chen","year":"2004","journal-title":"Development"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0092-8674(00)80678-9","article-title":"Hedgehog-regulated processing of Gli3 produces an anterior\/posterior repressor gradient in the developing vertebrate limb","volume":"100","author":"B Wang","year":"2000","journal-title":"Cell"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"8143","DOI":"10.1074\/jbc.274.12.8143","article-title":"Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3","volume":"274","author":"P Dai","year":"1999","journal-title":"J Biol Chem"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/j.1440-169X.2005.00837.x","article-title":"Further extension of mammalian GATA-6","volume":"47","author":"M Maeda","year":"2005","journal-title":"Dev Growth Differ"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"3905","DOI":"10.1242\/dev.080440","article-title":"Combinatorial regulation of tissue specification by GATA and FOG factors","volume":"139","author":"TM Chlon","year":"2012","journal-title":"Development"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"5161","DOI":"10.1242\/dev.128.24.5161","article-title":"Gli1 can rescue the in vivo function of Gli2","volume":"128","author":"CB Bai","year":"2001","journal-title":"Development"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1242\/dev.02395","article-title":"Pbx1\/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression","volume":"133","author":"TD Capellini","year":"2006","journal-title":"Development"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"e1000901","DOI":"10.1371\/journal.pgen.1000901","article-title":"Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development","volume":"6","author":"A Galli","year":"2010","journal-title":"PLoS Genet"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1126\/science.1096049","article-title":"A dual role for Hox genes in limb anterior-posterior asymmetry","volume":"304","author":"J Zakany","year":"2004","journal-title":"Science"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1242\/dev.125.14.2711","article-title":"Mutations in mouse Aristaless-like4 cause Strong&apos;s luxoid polydactyly","volume":"125","author":"S Qu","year":"1998","journal-title":"Development"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1210\/me.2007-0513","article-title":"Role of the GATA family of transcription factors in endocrine development, function, and disease","volume":"22","author":"RS Viger","year":"2008","journal-title":"Mol Endocrinol"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/79916","article-title":"Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3","volume":"3","author":"Y Litingtung","year":"2000","journal-title":"Nat Neurosci"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.1242\/dev.129.21.4963","article-title":"Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling","volume":"129","author":"M Rallu","year":"2002","journal-title":"Development"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1006\/bbrc.1998.9374","article-title":"Selection of DNA binding sites for human transcriptional regulator GATA-6","volume":"250","author":"Y Sakai","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1471-213X-12-23","article-title":"Conserved cis-regulatory regions in a large genomic landscape control SHH and BMP-regulated Gremlin1 expression in mouse limb buds","volume":"12","author":"A Zuniga","year":"2012","journal-title":"BMC Dev Biol"},{"key":"ref56","article-title":"Nkx3.2 maintains competence of somites to respond to Shh by blocking BMP-mediated induction of GATA4\/5\/6","author":"G Daoud"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"4753","DOI":"10.1242\/dev.129.20.4753","article-title":"Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway","volume":"129","author":"CB Bai","year":"2002","journal-title":"Development"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"4775","DOI":"10.1242\/dev.127.22.4775","article-title":"Sonic hedgehog regulates growth and morphogenesis of the tooth","volume":"127","author":"HR Dassule","year":"2000","journal-title":"Development"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1101\/gad.1008002","article-title":"Shh establishes an Nkx3.2\/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis","volume":"16","author":"L Zeng","year":"2002","journal-title":"Genes Dev"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"5021","DOI":"10.1242\/dev.124.24.5021","article-title":"Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En-1 mutants","volume":"124","author":"JA Cygan","year":"1997","journal-title":"Development"},{"key":"ref61","doi-asserted-by":"crossref","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":"A Bandyopadhyay","year":"2006","journal-title":"PLoS Genet"},{"key":"ref62","doi-asserted-by":"crossref","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":"LV Goodrich","year":"1996","journal-title":"Genes Dev"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/371609a0","article-title":"A positive feedback loop coordinates growth and patterning in the vertebrate limb","volume":"371","author":"L Niswander","year":"1994","journal-title":"Nature"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-60327-483-8_5","article-title":"Analysis of skeletal ontogenesis through differential staining of bone and cartilage","volume":"461","author":"MJ Depew","year":"2008","journal-title":"Methods Mol Biol"},{"key":"ref65","doi-asserted-by":"crossref","first-page":"11639","DOI":"10.1074\/jbc.M006564200","article-title":"PTHrP modulates chondrocyte differentiation through AP-1 and CREB signaling","volume":"276","author":"AM Ionescu","year":"2001","journal-title":"J Biol Chem"},{"key":"ref66","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1101\/gad.1693008","article-title":"A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb","volume":"22","author":"SA Vokes","year":"2008","journal-title":"Genes Dev"}],"container-title":["PLoS Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pgen.1004072","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T22:07:47Z","timestamp":1647986867000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1004072"}},"subtitle":[],"editor":[{"given":"Andrew O. M.","family":"Wilkie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2014,1,9]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,1,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1004072","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,9]]}}}