{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:46:49Z","timestamp":1790034409757,"version":"4.0.1"},"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2011,12,29]],"date-time":"2011-12-29T00:00:00Z","timestamp":1325116800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0028616","type":"journal-article","created":{"date-parts":[[2011,12,29]],"date-time":"2011-12-29T21:42:28Z","timestamp":1325194948000},"page":"e28616","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":62,"title":["DNaseI Hypersensitivity and Ultraconservation Reveal Novel, Interdependent Long-Range Enhancers at the Complex Pax6 Cis-Regulatory Region"],"prefix":"10.1371","volume":"6","author":[{"given":"David J.","family":"McBride","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Buckle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"van Heyningen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk A.","family":"Kleinjan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2011,12,29]]},"reference":[{"key":"ref1","article-title":"The Regulatory Genome.","author":"EH Davidson","year":"2006"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.genom.7.080505.115623","article-title":"Transcriptional regulatory elements in the human genome.","volume":"7","author":"GA Maston","year":"2006","journal-title":"Annu Rev Genomics Hum Genet"},{"issue":"1","key":"ref3","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1086\/426833","article-title":"Long-range control of gene expression: emerging mechanisms and disruption in disease.","volume":"76","author":"DA Kleinjan","year":"2005","journal-title":"Am J Hum Genet"},{"issue":"4","key":"ref4","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/bfgp\/elp022","article-title":"Cis-ruption mechanisms: disruption of cis-regulatory control as a cause of human genetic disease.","volume":"8","author":"DJ Kleinjan","year":"2009","journal-title":"Brief Funct Genomic Proteomic"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1242\/dev.113.4.1435","article-title":"Pax-6, a murine paired box gene, is expressed in the developing CNS.","volume":"113","author":"C Walther","year":"1991","journal-title":"Development"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1523\/JNEUROSCI.14-03-01395.1994","article-title":"Roles of Pax-genes in developing and adult brain as suggested by expression patterns.","volume":"14","author":"A Stoykova","year":"1994","journal-title":"J Neurosci"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1242\/dev.121.5.1433","article-title":"The role of Pax-6 in eye and nasal development.","volume":"121","author":"JC Grindley","year":"1995","journal-title":"Development"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1002\/bies.10174","article-title":"Pax6; a pleiotropic player in development.","volume":"24","author":"TI Simpson","year":"2002","journal-title":"Bioessays"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1242\/dev.124.8.1573","article-title":"Roles of Pax-6 in murine diencephalic development.","volume":"124","author":"N Warren","year":"1997","journal-title":"Development"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0925-4773(99)00324-X","article-title":"Pax genes and the differentiation of hormone-producing endocrine cells in the pancreas.","volume":"92","author":"C Dohrmann","year":"2000","journal-title":"Mech Dev"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/387406a0","article-title":"Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas.","volume":"387","author":"L St-Onge","year":"1997","journal-title":"Nature"},{"issue":"21","key":"ref12","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1101\/gad.184000","article-title":"Pax6 activity in the lens primordium is required for lens formation and for correct placement of a single retina in the eye.","volume":"14","author":"R Ashery-Padan","year":"2000","journal-title":"Genes Dev"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"3453","DOI":"10.1242\/dev.122.11.3453","article-title":"Forebrain patterning defects in Small eye mutant mice.","volume":"122","author":"A Stoykova","year":"1996","journal-title":"Development"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1006\/mcne.2000.0924","article-title":"Pax6 regulates the identity of embryonic diencephalic neurons.","volume":"17","author":"GS Mastick","year":"2001","journal-title":"Mol Cell Neurosci"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1093\/cercor\/9.6.627","article-title":"The transcription factor, Pax6, is required for cell proliferation and differentiation in the developing cerebral cortex.","volume":"9","author":"N Warren","year":"1999","journal-title":"Cereb Cortex"},{"issue":"25","key":"ref16","doi-asserted-by":"crossref","first-page":"14378","DOI":"10.1073\/pnas.96.25.14378","article-title":"Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development.","volume":"96","author":"C Kioussi","year":"1999","journal-title":"Proc Natl Acad Sci USA;"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"3585","DOI":"10.1242\/dev.126.16.3585","article-title":"Role of Pax6 in development of the cerebellar system.","volume":"126","author":"D Engelkamp","year":"1999","journal-title":"Development"},{"issue":"1","key":"ref18","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0092-8674(01)00295-1","article-title":"Pax6 is required for the multipotent state of retinal progenitor cells.","volume":"105","author":"T Marquardt","year":"2001","journal-title":"Cell"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/0092-8674(91)90284-6","article-title":"Positional cloning and characterization of a paired box-containing and homeobox-containing gene from the aniridia region.","volume":"67","author":"CCT Ton","year":"1991","journal-title":"Cell"},{"key":"ref20","first-page":"95","article-title":"Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse.","volume":"97","author":"BL Hogan","year":"1986","journal-title":"J Embryol Exp Morphol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/354522a0","article-title":"Mouse small eye results from mutations in a paired-like homeobox-containing gene.","volume":"354","author":"RE Hill","year":"1991","journal-title":"Nature"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/90042","article-title":"PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.","volume":"28","author":"SM Sisodiya","year":"2001","journal-title":"Nature Genetics"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0092-8674(00)80078-1","article-title":"Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities.","volume":"86","author":"A Schedl","year":"1996","journal-title":"Cell"},{"issue":"3","key":"ref24","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1242\/dev.02764","article-title":"Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization.","volume":"134","author":"M Manuel","year":"2007","journal-title":"Development"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/1471-213X-8-59","article-title":"Overexpression of Pax6 results in microphthalmia, retinal dysplasia and defective retinal ganglion cell axon guidance.","volume":"8","author":"M Manuel","year":"2008","journal-title":"BMC Dev Biol"},{"issue":"9","key":"ref26","doi-asserted-by":"crossref","first-page":"4045","DOI":"10.1167\/iovs.07-1630","article-title":"Effects of elevated Pax6 expression and genetic background on mouse eye development.","volume":"50","author":"SA Chanas","year":"2009","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"2","key":"ref27","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0925-4773(98)00057-4","article-title":"A highly conserved lens transcriptional control element from the Pax-6 gene.","volume":"73","author":"SC Williams","year":"1998","journal-title":"Mech Dev"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1006\/dbio.1998.9128","article-title":"Distinct cis-essential modules direct the time-space pattern of the Pax6 gene activity.","volume":"205","author":"B Kammandel","year":"1999","journal-title":"Dev Biol"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1242\/dev.126.2.383","article-title":"Regulation of Pax6 expression is conserved between mice and flies.","volume":"126","author":"PX Xu","year":"1999","journal-title":"Development"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1093\/hmg\/10.19.2049","article-title":"Aniridia-associated translocations, DNase hypersensitivity, sequence comparison and transgenic analysis redefine the functional domain of PAX6.","volume":"10","author":"DA Kleinjan","year":"2001","journal-title":"Hum Mol Genet"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0925-4773(01)00646-3","article-title":"New 3\u2032 elements control Pax6 expression in the developing pretectum, neural retina and olfactory region.","volume":"112","author":"C Griffin","year":"2002","journal-title":"Mech Dev"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ydbio.2003.09.011","article-title":"Conserved elements in Pax6 intron 7 involved in (auto)regulation and alternative transcription.","volume":"265","author":"DA Kleinjan","year":"2004","journal-title":"Dev Biol"},{"issue":"2","key":"ref33","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.ydbio.2006.08.060","article-title":"Long-range downstream enhancers are essential for Pax6 expression.","volume":"299","author":"DA Kleinjan","year":"2006","journal-title":"Dev Biol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/BF00291536","article-title":"Familial aniridia and translocation t(4;11)(q22;p13) without Wilms' tumor.","volume":"63","author":"KO Simola","year":"1983","journal-title":"Hum. Genet"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1093\/hmg\/4.3.415","article-title":"Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype.","volume":"4","author":"J Fantes","year":"1995","journal-title":"Hum Mol Genet"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"13755","DOI":"10.1073\/pnas.240398797","article-title":"3\u2032 deletions cause aniridia by preventing PAX6 gene expression.","volume":"97","author":"JD Lauderdale","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"ref37","first-page":"e29","article-title":"PLoS Genet","volume":"4","author":"DA Kleinjan","year":"2008","journal-title":"PLoS Genet"},{"issue":"6","key":"ref38","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/nrg1350","article-title":"Comparative genomics at the vertebrate extremes.","volume":"5","author":"D Boffelli","year":"2004","journal-title":"Nat Rev Genet"},{"issue":"2","key":"ref39","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1101\/gr.6929408","article-title":"Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b.","volume":"18","author":"DM McGaughey","year":"2008","journal-title":"Genome Res"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1146\/annurev.bi.57.070188.001111","article-title":"Nuclease hypersensitive sites in chromatin.","volume":"57","author":"DS Gross","year":"1988","journal-title":"Annu.Rev.Biochem"},{"issue":"36","key":"ref41","doi-asserted-by":"crossref","first-page":"19259","DOI":"10.1016\/S0021-9258(19)77625-X","article-title":"The formation and function of DNase I hypersensitive sites in the process of gene activation.","volume":"263","author":"SC Elgin","year":"1988","journal-title":"J Biol Chem"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1101\/gr.10.4.577","article-title":"PipMaker--a web server for aligning two genomic DNA sequences.","volume":"10","author":"S Schwartz","year":"2000","journal-title":"Genome Res"},{"issue":"2","key":"ref43","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.ydbio.2005.12.041","article-title":"Analysis of Pax6 expression using a BAC transgene reveals the presence of a paired-less isoform of Pax6 in the eye and olfactory bulb.","volume":"292","author":"J Kim","year":"2006","journal-title":"Dev Biol"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/0092-8674(94)90553-3","article-title":"Mice lacking vimentin develop and reproduce without an obvious phenotype.","volume":"79","author":"E Colucci-Guyon","year":"1994","journal-title":"Cell"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1073\/pnas.65.1.129","article-title":"Isolation of microtubule protein from cultured mouse neuroblastoma cells. Proc.","volume":"65","author":"JB Olmsted","year":"1970","journal-title":"Natl. Acad. Sci. U. S. A"},{"key":"ref46","first-page":"319","article-title":"Electron microscope observations on virus particles associated with a transplantable renal adenocarcinoma in BALB-cf-Cd mice.","volume":"43","author":"B Felluga","year":"1969","journal-title":"J Natl. Cancer Inst"},{"issue":"10","key":"ref47","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1101\/gr.3783805","article-title":"Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements.","volume":"15","author":"FM Pauler","year":"2005","journal-title":"Genome Res"},{"issue":"7052","key":"ref48","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1038\/nature03877","article-title":"A high-resolution map of active promoters in the human genome.","volume":"436","author":"TH Kim","year":"2005","journal-title":"Nature"},{"key":"ref49","article-title":"Development of the cerebellar system; in relation to its evolution, structure and functions.","author":"J Altman","year":"1997"},{"issue":"6","key":"ref50","doi-asserted-by":"crossref","first-page":"e1002099","DOI":"10.1371\/journal.pgen.1002099","article-title":"A novel approach to selectively target neuronal subpopulations reveals genetic pathways that regulate tangential migration in the vertebrate hindbrain.","volume":"7","author":"K Benzing","year":"2011","journal-title":"PLoS Genet"},{"issue":"5675","key":"ref51","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1126\/science.1098119","article-title":"Ultraconserved elements in the human genome.","volume":"304","author":"G Bejerano","year":"2004","journal-title":"Science"},{"issue":"6","key":"ref52","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.neuron.2005.11.031","article-title":"Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by Pax6.","volume":"48","author":"RL Landsberg","year":"2005","journal-title":"Neuron"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1471-213X-6-21","article-title":"Functional conservation of Pax6 regulatory elements in humans and mice demonstrated with a novel transgenic reporter mouse.","volume":"6","author":"DA Tyas","year":"2006","journal-title":"BMC Dev Biol"},{"issue":"2","key":"ref54","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/nrg2499","article-title":"The evolution of hierarchical gene regulatory networks.","volume":"10","author":"DH Erwin","year":"2009","journal-title":"Nat Rev Genet"},{"issue":"15","key":"ref55","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1242\/dev.032888","article-title":"Pax6 is essential for lens fiber cell differentiation.","volume":"136","author":"O Shaham","year":"2009","journal-title":"Development"},{"issue":"4","key":"ref56","doi-asserted-by":"crossref","first-page":"R146","DOI":"10.1016\/j.cub.2011.01.005","article-title":"Maintaining a memory by transcriptional autoregulation.","volume":"21","author":"O Hobert","year":"2011","journal-title":"Curr Biol"},{"issue":"10","key":"ref57","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1101\/gr.108795.110","article-title":"Massive turnover of functional sequence in human and other mammalian genomes.","volume":"20","author":"S Meader","year":"2010","journal-title":"Genome Res"},{"issue":"12","key":"ref58","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/j.jocn.2009.03.022","article-title":"A novel heterozygous deletion within the 3\u2032 region of the PAX6 gene causing isolated aniridia in a large family group.","volume":"16","author":"F Bayrakli","year":"2009","journal-title":"J Clin.Neurosci"},{"issue":"17","key":"ref59","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1016\/j.cub.2010.07.043","article-title":"Shadow enhancers foster robustness of Drosophila gastrulation.","volume":"20","author":"MW Perry","year":"2010","journal-title":"Curr Biol"},{"issue":"7305","key":"ref60","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nature09158","article-title":"Phenotypic robustness conferred by apparently redundant transcriptional enhancers.","volume":"466","author":"N Frankel","year":"2010","journal-title":"Nature"},{"issue":"50","key":"ref61","doi-asserted-by":"crossref","first-page":"21931","DOI":"10.1073\/pnas.1016071107","article-title":"Histone H3K27ac separates active from poised enhancers and predicts developmental state.","volume":"107","author":"MP Creyghton","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"W273","DOI":"10.1093\/nar\/gkh458","article-title":"VISTA: computational tools for comparative genomics.","volume":"32","author":"KA Frazer","year":"2004","journal-title":"Nucleic Acids Res"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0028616","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T21:25:09Z","timestamp":1640294709000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0028616"}},"subtitle":[],"editor":[{"given":"Sheng-Ping Lucinda","family":"Hwang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2011,12,29]]},"references-count":62,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2011,12,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0028616","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12,29]]}}}