{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T08:40:04Z","timestamp":1789029604819,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010092","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T00:00:00Z","timestamp":1646870400000}}],"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Food and Health Bureau of Hong Kong","award":["07183186"],"award-info":[{"award-number":["07183186"]}]},{"DOI":"10.13039\/501100002920","name":"Research Grants Council, University Grants Committee","doi-asserted-by":"publisher","award":["ECS 27104219"],"award-info":[{"award-number":["ECS 27104219"]}],"id":[{"id":"10.13039\/501100002920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002920","name":"Research Grants Council, University Grants Committee","doi-asserted-by":"publisher","award":["GRF 17107021"],"award-info":[{"award-number":["GRF 17107021"]}],"id":[{"id":"10.13039\/501100002920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002920","name":"Research Grants Council, University Grants Committee","doi-asserted-by":"publisher","award":["CRF C7026-20G"],"award-info":[{"award-number":["CRF C7026-20G"]}],"id":[{"id":"10.13039\/501100002920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003802","name":"University Research Committee, University of Hong Kong","doi-asserted-by":"publisher","award":["seed fund 201910159087 and 202011159053"],"award-info":[{"award-number":["seed fund 201910159087 and 202011159053"]}],"id":[{"id":"10.13039\/501100003802","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["Excellent Young Scientists Fund Hong Kong and Macau"],"award-info":[{"award-number":["Excellent Young Scientists Fund Hong Kong and Macau"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Hox genes encode evolutionarily conserved transcription factors that specify regional identities along the anterior-posterior (A-P) axis. Although some Hox genes are known to regulate the differentiation of certain neurons, to what extent Hox genes are involved in the terminal specification of the entire nervous system is unclear. Here, we systematically mapped the expression of all six Hox genes in <jats:italic>C<\/jats:italic>. <jats:italic>elegans<\/jats:italic> nervous system and found Hox expression in 97 (32%) of the 302 neurons in adult hermaphrodites. Our results are generally consistent with previous high-throughput expression mapping and single-cell transcriptomic studies. Detailed analysis of the fate markers for these neurons revealed that Hox genes regulate the differentiation of 29 (25%) of the 118 classes of <jats:italic>C<\/jats:italic>. <jats:italic>elegans<\/jats:italic> neurons. Hox genes not only regulate the specification of terminal neuronal fates through multiple mechanisms but also control subtype diversification along the A-P axis. The widespread involvement of Hox genes in neuronal differentiation indicates their roles in establishing complex nervous systems.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010092","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T18:34:25Z","timestamp":1646073265000},"page":"e1010092","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Nervous system-wide analysis of Hox regulation of terminal neuronal fate specification in Caenorhabditis elegans"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5048-4520","authenticated-orcid":true,"given":"Chaogu","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3376-371X","authenticated-orcid":true,"given":"Ho Ming Terence","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Pham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"issue":"1","key":"pgen.1010092.ref001","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0092-8674(83)90204-0","article-title":"Different requirements for homeotic genes in the soma and germ line of Drosophila","volume":"35","author":"PA Lawrence","year":"1983","journal-title":"Cell"},{"issue":"4","key":"pgen.1010092.ref002","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/bies.950140408","article-title":"Evolution of the vertebrate Hox homeobox genes","volume":"14","author":"R. Krumlauf","year":"1992","journal-title":"Bioessays"},{"issue":"3","key":"pgen.1010092.ref003","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/genetics\/114.3.919","article-title":"The relationship between the functional complexity and the molecular organization of the Antennapedia locus of Drosophila melanogaster","volume":"114","author":"MK Abbott","year":"1986","journal-title":"Genetics"},{"issue":"5824","key":"pgen.1010092.ref004","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/292635a0","article-title":"A homoeotic mutation transforming leg to antenna in Drosophila","volume":"292","author":"G. Struhl","year":"1981","journal-title":"Nature"},{"issue":"1","key":"pgen.1010092.ref005","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ydbio.2011.02.015","article-title":"Segment-specific generation of Drosophila Capability neuropeptide neurons by multi-faceted Hox cues","volume":"353","author":"A Suska","year":"2011","journal-title":"Dev Biol"},{"issue":"3","key":"pgen.1010092.ref006","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.neuron.2015.09.049","article-title":"Hox Genes Promote Neuronal Subtype Diversification through Posterior Induction in Caenorhabditis elegans","volume":"88","author":"C Zheng","year":"2015","journal-title":"Neuron"},{"issue":"7","key":"pgen.1010092.ref007","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1016\/j.celrep.2015.10.044","article-title":"Hox Proteins Act as Transcriptional Guarantors to Ensure Terminal Differentiation","volume":"13","author":"C Zheng","year":"2015","journal-title":"Cell Rep"},{"issue":"6200","key":"pgen.1010092.ref008","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/336638a0","article-title":"A genetic pathway for the development of the Caenorhabditis elegans HSN motor neurons","volume":"336","author":"C Desai","year":"1988","journal-title":"Nature"},{"key":"pgen.1010092.ref009","first-page":"6","article-title":"An intersectional gene regulatory strategy defines subclass diversity of C. elegans motor neurons","author":"P Kratsios","year":"2017","journal-title":"Elife"},{"issue":"1","key":"pgen.1010092.ref010","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neuron.2013.09.020","article-title":"Hox genes: choreographers in neural development, architects of circuit organization","volume":"80","author":"P Philippidou","year":"2013","journal-title":"Neuron"},{"key":"pgen.1010092.ref011","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/1471-213X-10-78","article-title":"The C. elegans Hox gene ceh-13 regulates cell migration and fusion in a non-colinear way. Implications for the early evolution of Hox clusters","volume":"10","author":"B Tihanyi","year":"2010","journal-title":"BMC Dev Biol"},{"issue":"6012","key":"pgen.1010092.ref012","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1126\/science.1196914","article-title":"Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project","volume":"330","author":"MB Gerstein","year":"2010","journal-title":"Science"},{"issue":"9","key":"pgen.1010092.ref013","doi-asserted-by":"crossref","first-page":"e1001089","DOI":"10.1371\/journal.pgen.1001089","article-title":"A negative regulatory loop between microRNA and Hox gene controls posterior identities in Caenorhabditis elegans","volume":"6","author":"Z Zhao","year":"2010","journal-title":"PLoS Genet"},{"issue":"7822","key":"pgen.1010092.ref014","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/s41586-020-2618-9","article-title":"Unique homeobox codes delineate all the neuron classes of C. elegans","volume":"584","author":"MB Reilly","year":"2020","journal-title":"Nature"},{"issue":"16","key":"pgen.1010092.ref015","doi-asserted-by":"crossref","first-page":"4329","DOI":"10.1016\/j.cell.2021.06.023","article-title":"Molecular topography of an entire nervous system","volume":"184","author":"SR Taylor","year":"2021","journal-title":"Cell"},{"issue":"1","key":"pgen.1010092.ref016","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.cell.2020.12.012","article-title":"NeuroPAL: A Multicolor Atlas for Whole-Brain Neuronal Identification in C. elegans","volume":"184","author":"E Yemini","year":"2021","journal-title":"Cell"},{"issue":"6459","key":"pgen.1010092.ref017","doi-asserted-by":"crossref","DOI":"10.1126\/science.aax1971","article-title":"A lineage-resolved molecular atlas of C. elegans embryogenesis at single-cell resolution","volume":"365","author":"JS Packer","year":"2019","journal-title":"Science"},{"issue":"1","key":"pgen.1010092.ref018","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0092-8674(93)90293-Y","article-title":"Control of cell fates in the central body region of C. elegans by the homeobox gene lin-39","volume":"74","author":"SG Clark","year":"1993","journal-title":"Cell"},{"issue":"27","key":"pgen.1010092.ref019","doi-asserted-by":"crossref","first-page":"11175","DOI":"10.1073\/pnas.1301849110","article-title":"Transmembrane protein MIG-13 links the Wnt signaling and Hox genes to the cell polarity in neuronal migration","volume":"110","author":"X Wang","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6357","key":"pgen.1010092.ref020","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/355255a0","article-title":"Activation of a C. elegans Antennapedia homologue in migrating cells controls their direction of migration","volume":"355","author":"SJ Salser","year":"1992","journal-title":"Nature"},{"issue":"1","key":"pgen.1010092.ref021","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ydbio.2010.05.502","article-title":"Time-lapse imaging and cell-specific expression profiling reveal dynamic branching and molecular determinants of a multi-dendritic nociceptor in C. elegans","volume":"345","author":"CJ Smith","year":"2010","journal-title":"Dev Biol"},{"issue":"22","key":"pgen.1010092.ref022","article-title":"Inhibition of cell fate repressors secures the differentiation of the touch receptor neurons of Caenorhabditis elegans","volume":"145","author":"C Zheng","year":"2018","journal-title":"Development"},{"issue":"1","key":"pgen.1010092.ref023","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ydbio.2016.07.018","article-title":"The C. elegans hox gene lin-39 controls cell cycle progression during vulval development","volume":"418","author":"D Roiz","year":"2016","journal-title":"Dev Biol"},{"issue":"10","key":"pgen.1010092.ref024","doi-asserted-by":"crossref","first-page":"3790","DOI":"10.1073\/pnas.0712159105","article-title":"A Caenorhabditis elegans model for epithelial-neuronal transdifferentiation","volume":"105","author":"S Jarriault","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pgen.1010092.ref025","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1534\/genetics.108.088948","article-title":"The T-box gene tbx-2, the homeobox gene egl-5 and the asymmetric cell division gene ham-1 specify neural fate in the HSN\/PHB lineage","volume":"179","author":"A Singhvi","year":"2008","journal-title":"Genetics"},{"issue":"1","key":"pgen.1010092.ref026","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/0012-1606(77)90158-0","article-title":"Post-embryonic cell lineages of the nematode, Caenorhabditis elegans","volume":"56","author":"JE Sulston","year":"1977","journal-title":"Dev Biol"},{"issue":"4","key":"pgen.1010092.ref027","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1002\/cne.20189","article-title":"Expression and regulation of an FMRFamide-related neuropeptide gene family in Caenorhabditis elegans","volume":"475","author":"K Kim","year":"2004","journal-title":"J Comp Neurol"},{"issue":"1","key":"pgen.1010092.ref028","article-title":"\u2019Meara B, Tucker DK, Ackley BD. The Hox Gene egl-5 Acts as a Terminal Selector for VD13","volume":"8","author":"O Kurland M","year":"2020","journal-title":"Development via Wnt Signaling. J Dev Biol"},{"issue":"9","key":"pgen.1010092.ref029","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.1073\/pnas.97.9.4499","article-title":"Caenorhabditis elegans embryonic axial patterning requires two recently discovered posterior-group Hox genes","volume":"97","author":"K Van Auken","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pgen.1010092.ref030","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.cub.2005.02.025","article-title":"Expression profiling of GABAergic motor neurons in Caenorhabditis elegans","volume":"15","author":"H Cinar","year":"2005","journal-title":"Curr Biol"},{"issue":"2","key":"pgen.1010092.ref031","doi-asserted-by":"crossref","first-page":"e1003252","DOI":"10.1371\/journal.pgen.1003252","article-title":"Antagonism versus cooperativity with TALE cofactors at the base of the functional diversification of Hox protein function","volume":"9","author":"ML Rivas","year":"2013","journal-title":"PLoS Genet"},{"issue":"14","key":"pgen.1010092.ref032","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1128\/MCB.00889-09","article-title":"Pbx1 represses osteoblastogenesis by blocking Hoxa10-mediated recruitment of chromatin remodeling factors","volume":"30","author":"JA Gordon","year":"2010","journal-title":"Mol Cell Biol"},{"issue":"1165","key":"pgen.1010092.ref033","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1098\/rstb.1986.0056","article-title":"The structure of the nervous system of the nematode Caenorhabditis elegans","volume":"314","author":"JG White","year":"1986","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"issue":"22","key":"pgen.1010092.ref034","doi-asserted-by":"crossref","first-page":"8623","DOI":"10.1128\/MCB.20.22.8623-8633.2000","article-title":"Cell signaling switches HOX-PBX complexes from repressors to activators of transcription mediated by histone deacetylases and histone acetyltransferases","volume":"20","author":"M Saleh","year":"2000","journal-title":"Mol Cell Biol"},{"issue":"1","key":"pgen.1010092.ref035","doi-asserted-by":"crossref","first-page":"e1003184","DOI":"10.1371\/journal.pgen.1003184","article-title":"Genetic and functional modularity of Hox activities in the specification of limb-innervating motor neurons","volume":"9","author":"J Lacombe","year":"2013","journal-title":"PLoS Genet"},{"issue":"1","key":"pgen.1010092.ref036","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","article-title":"The genetics of Caenorhabditis elegans","volume":"77","author":"S. Brenner","year":"1974","journal-title":"Genetics"},{"issue":"12","key":"pgen.1010092.ref037","doi-asserted-by":"crossref","first-page":"e1004017","DOI":"10.1371\/journal.pgen.1004017","article-title":"Histone methylation restrains the expression of subtype-specific genes during terminal neuronal differentiation in Caenorhabditis elegans","volume":"9","author":"C Zheng","year":"2013","journal-title":"PLoS Genet"},{"issue":"3","key":"pgen.1010092.ref038","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1534\/genetics.118.301532","article-title":"Robust Genome Editing with Short Single-Stranded and Long, Partially Single-Stranded DNA Donors in Caenorhabditis elegans","volume":"210","author":"GA Dokshin","year":"2018","journal-title":"Genetics"},{"key":"pgen.1010092.ref039","first-page":"5","article-title":"A cellular and regulatory map of the GABAergic nervous system of C. elegans","author":"M Gendrel","year":"2016","journal-title":"Elife"},{"key":"pgen.1010092.ref040","first-page":"4","article-title":"A cellular and regulatory map of the cholinergic nervous system of C. elegans","author":"L Pereira","year":"2015","journal-title":"Elife"},{"issue":"3","key":"pgen.1010092.ref041","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.cell.2013.09.052","article-title":"Modular control of glutamatergic neuronal identity in C. elegans by distinct homeodomain proteins","volume":"155","author":"E Serrano-Saiz","year":"2013","journal-title":"Cell"},{"issue":"7240","key":"pgen.1010092.ref042","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nature07929","article-title":"Gene regulatory logic of dopamine neuron differentiation","volume":"458","author":"N Flames","year":"2009","journal-title":"Nature"},{"issue":"1","key":"pgen.1010092.ref043","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1534\/genetics.107.079780","article-title":"Regulation of serotonin biosynthesis by the G proteins Galphao and Galphaq controls serotonin signaling in Caenorhabditis elegans","volume":"178","author":"JE Tanis","year":"2008","journal-title":"Genetics"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1010092","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T00:00:00Z","timestamp":1646870400000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1010092","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T19:00:25Z","timestamp":1646938825000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1010092"}},"subtitle":[],"editor":[{"given":"Andrew D.","family":"Chisholm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,28]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1010092","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pgen.1010092","asserted-by":"object"}]},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,28]]}}}