{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T14:38:30Z","timestamp":1768315110460,"version":"3.49.0"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T00:00:00Z","timestamp":1620604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Sophisticated axolotl limb regeneration is a highly orchestrated process that requires highly regulated gene expression and epigenetic modification patterns at precise positions and timings. We previously demonstrated two waves of post-amputation expression of a nerve-mediated repressive epigenetic modulator, histone deacetylase 1 (HDAC1), at the wound healing (3 days post-amputation; 3 dpa) and blastema formation (8 dpa onward) stages in juvenile axolotls. Limb regeneration was profoundly inhibited by local injection of an HDAC inhibitor, MS-275, at the amputation sites. To explore the transcriptional response of post-amputation axolotl limb regeneration in a tissue-specific and time course-dependent manner after MS-275 treatment, we performed transcriptome sequencing of the epidermis and soft tissue (ST) at 0, 3, and 8 dpa with and without MS-275 treatment. Gene Ontology (GO) enrichment analysis of each coregulated gene cluster revealed a complex array of functional pathways in both the epidermis and ST. In particular, HDAC activities were required to inhibit the premature elevation of genes related to tissue development, differentiation, and morphogenesis. Further validation by Q-PCR in independent animals demonstrated that the expression of 5 out of 6 development- and regeneration-relevant genes that should only be elevated at the blastema stage was indeed prematurely upregulated at the wound healing stage when HDAC1 activity was inhibited. WNT pathway-associated genes were also prematurely activated under HDAC1 inhibition. Applying a WNT inhibitor to MS-275-treated amputated limbs partially rescued HDAC1 inhibition, resulting in blastema formation defects. We propose that post-amputation HDAC1 expression is at least partially responsible for pacing the expression timing of morphogenic genes to facilitate proper limb regeneration.<\/jats:p>","DOI":"10.3389\/fcell.2021.641987","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T08:10:04Z","timestamp":1620634204000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Timing Does Matter: Nerve-Mediated HDAC1 Paces the Temporal Expression of Morphogenic Genes During Axolotl Limb Regeneration"],"prefix":"10.3389","volume":"9","author":[{"given":"Mu-Hui","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Lang","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Han","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling-Ling","family":"Chiou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Tzang","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsuan-Shu","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shau-Ping","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool.","volume":"215","author":"Altschul","year":"1990","journal-title":"J. Mol. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1007\/bf00399054","article-title":"In vitro control of blastema cell proliferation by extracts from epidermal cap and mesenchyme of regenerating limbs of axolotls.","volume":"198","author":"Boilly","year":"1990","journal-title":"Roux Arch. Dev. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1016\/j.celrep.2016.12.063","article-title":"A tissue-mapped axolotl de novo transcriptome enables identification of limb regeneration factors.","volume":"18","author":"Bryant","year":"2017","journal-title":"Cell Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1002\/dvdy.22669","article-title":"Gene expression profile of the regeneration epithelium during axolotl limb regeneration.","volume":"240","author":"Campbell","year":"2011","journal-title":"Dev. Dyn."},{"key":"B5","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/0012-1606(75)90282-1","article-title":"The effects of rotation and positional change of stump tissues upon morphogenesis of the regenerating axolotl limb.","volume":"47","author":"Carlson","year":"1975","journal-title":"Dev. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/jmor.1050940103","article-title":"A quantitative histological analysis of forelimb regeneration triturus viridescens.","volume":"94","author":"Chalkley","year":"1954","journal-title":"J. Morphol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.devcel.2016.10.013","article-title":"Live imaging of Axolotl digit regeneration reveals spatiotemporal choreography of diverse connective tissue progenitor pools.","volume":"39","author":"Currie","year":"2016","journal-title":"Dev. Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e4004","DOI":"10.7717\/peerj.4004","article-title":"Transcriptome dynamics along axolotl regenerative development are consistent with an extensive reduction in gene expression heterogeneity in dedifferentiated cells.","volume":"5","author":"D\u00edaz-Castillo","year":"2017","journal-title":"PeerJ"},{"key":"B9","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/0012-1606(77)90157-9","article-title":"The role of grafted skin in the regeneration of X-irradiated axolotl limbs.","volume":"56","author":"Dunis","year":"1977","journal-title":"Dev. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3439","DOI":"10.1093\/bioinformatics\/bti525","article-title":"BioMart and Bioconductor: a powerful link between biological databases and microarray data analysis.","volume":"21","author":"Durinck","year":"2005","journal-title":"Bioinformatics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.ydbio.2004.02.016","article-title":"A stepwise model system for limb regeneration.","volume":"270","author":"Endo","year":"2004","journal-title":"Dev. Biol."},{"key":"B12","doi-asserted-by":"crossref","first-page":"16016","DOI":"10.1038\/npjregenmed.2016.16","article-title":"A novel role for SALL4 during scar-free wound healing in axolotl.","volume":"1","author":"Erickson","year":"2016","journal-title":"NPJ Regen. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"12501","DOI":"10.1073\/pnas.1706855114","article-title":"Efficient gene knockin in axolotl and its use to test the role of satellite cells in limb regeneration.","volume":"114","author":"Fei","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B14","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1111\/j.1440-169x.2010.01208.x","article-title":"Ex vivo generation of a functional and regenerative wound epithelium from axolotl (Ambystoma mexicanum) skin.","volume":"52","author":"Ferris","year":"2010","journal-title":"Dev. Growth Differ."},{"key":"B15","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1142\/s0219720005001375","article-title":"Noise-robust soft clustering of gene expression time-course data.","volume":"3","author":"Futschik","year":"2005","journal-title":"J. Bioinform. Comput. Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0074-7696(08)61769-6","article-title":"Gene expression during amphibian limb regeneration.","volume":"180","author":"Geraudie","year":"1998","journal-title":"Int. Rev. Cytol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"eaaq0681","DOI":"10.1126\/science.aaq0681","article-title":"Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration.","volume":"362","author":"Gerber","year":"2018","journal-title":"Science"},{"key":"B18","doi-asserted-by":"crossref","first-page":"5420","DOI":"10.1038\/sj.onc.1210610","article-title":"Histone deacetylases and cancer.","volume":"26","author":"Glozak","year":"2007","journal-title":"Oncogene"},{"key":"B19","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41536-017-0027-y","article-title":"Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape.","volume":"2","author":"Godwin","year":"2017","journal-title":"NPJ Regen."},{"key":"B20","doi-asserted-by":"publisher","first-page":"9415","DOI":"10.1073\/pnas.1300290110","article-title":"Macrophages are required for adult salamander limb regeneration.","volume":"110","author":"Godwin","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"B21","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/ar.1091260103","article-title":"Regenerative inhibition following limb amputation and immediate insertion into the body cavity.","volume":"126","author":"Goss","year":"1956","journal-title":"Anatomical Rec."},{"key":"B22","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/0012-1606(61)90009-4","article-title":"Origin of the blastema in regenerating limbs of the newt Triturus viridescens: an autoradiographic study using tritiated thymidine to follow cell proliferation and migration.","volume":"3","author":"Hay","year":"1961","journal-title":"Dev. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.ydbio.2015.08.013","article-title":"Epigenetic modification maintains intrinsic limb-cell identity in Xenopus limb bud regeneration.","volume":"406","author":"Hayashi","year":"2015","journal-title":"Dev. Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e61352","DOI":"10.1371\/journal.pone.0061352","article-title":"Comparative transcriptional profiling of the axolotl limb identifies a tripartite regeneration-specific gene program.","volume":"8","author":"Knapp","year":"2013","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/nature08152","article-title":"Cells keep a memory of their tissue origin during axolotl limb regeneration.","volume":"460","author":"Kragl","year":"2009","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.ydbio.2012.10.019","article-title":"Muscle and connective tissue progenitor populations show distinct Twist1 and Twist3 expression profiles during axolotl limb regeneration.","volume":"373","author":"Kragl","year":"2013","journal-title":"Dev. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2.","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"B28","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.1038\/s41467-018-07604-0","article-title":"Transcriptomic landscape of the blastema niche in regenerating adult axolotl limbs at single-cell resolution.","volume":"9","author":"Leigh","year":"2018","journal-title":"Nat. Commun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1186\/1471-2105-12-323","article-title":"RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome.","volume":"12","author":"Li","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"B30","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/s13238-020-00763-1","article-title":"Dynamic cell transition and immune response landscapes of axolotl limb regeneration revealed by single-cell analysis.","volume":"12","author":"Li","year":"2021","journal-title":"Protein Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/ncb1736","article-title":"Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells.","volume":"10","author":"Liang","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.ydbio.2013.05.010","article-title":"Nerve independent limb induction in axolotls.","volume":"381","author":"Makanae","year":"2013","journal-title":"Dev. Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ydbio.2014.09.021","article-title":"Co-operative Bmp- and Fgf-signaling inputs convert skin wound healing to limb formation in urodele amphibians.","volume":"396","author":"Makanae","year":"2014","journal-title":"Dev. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4288","DOI":"10.1093\/nar\/gks042","article-title":"Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation.","volume":"40","author":"McCarthy","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.ydbio.2016.05.032","article-title":"Cartilage and bone cells do not participate in skeletal regeneration in ambystoma mexicanum limbs.","volume":"416","author":"McCusker","year":"2016","journal-title":"Dev. Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e77064","DOI":"10.1371\/journal.pone.0077064","article-title":"Positional information is reprogrammed in blastema cells of the regenerating limb of the axolotl (Ambystoma mexicanum).","volume":"8","author":"McCusker","year":"2013","journal-title":"PLoS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1002\/jez.1401950111","article-title":"Effects on adult newt limb regeneration of partial and complete skin flaps over the amputation surface.","volume":"195","author":"Mescher","year":"1976","journal-title":"J. Exp. Zool."},{"key":"B38","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/b99966","article-title":"Regenerative capacity and the developing immune system.","volume":"93","author":"Mescher","year":"2005","journal-title":"Adv. Biochem. Eng. Biotechnol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1242\/bio.20121594","article-title":"Gene expression patterns specific to the regenerating limb of the mexican axolotl.","volume":"1","author":"Monaghan","year":"2012","journal-title":"Biol. Open"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1741-7007-7-1","article-title":"Microarray and cDNA sequence analysis of transcription during nerve-dependent limb regeneration.","volume":"7","author":"Monaghan","year":"2009","journal-title":"BMC Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/0012-1606(86)90062-x","article-title":"Cellular contribution from dermis and cartilage to the regenerating limb blastema in axolotls.","volume":"116","author":"Muneoka","year":"1986","journal-title":"Dev. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1242\/dev.081752","article-title":"Connective tissue cells, but not muscle cells, are involved in establishing the proximo-distal outcome of limb regeneration in the axolotl.","volume":"140","author":"Nacu","year":"2013","journal-title":"Development"},{"key":"B43","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature25458","article-title":"The axolotl genome and the evolution of key tissue formation regulators.","volume":"554","author":"Nowoshilow","year":"2018","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.ceb.2018.01.003","article-title":"Epigenetic basis of cellular plasticity.","volume":"49","author":"Paksa","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/0012-1606(80)90115-3","article-title":"The origin of skeletal structures during intercalary regeneration of larval ambystoma limbs.","volume":"79","author":"Pescitelli","year":"1980","journal-title":"Dev. Biol."},{"key":"B46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-03425-3","article-title":"Basal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal.","volume":"9","author":"Rayagiri","year":"2018","journal-title":"Nat. Commun."},{"key":"B47","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1101\/gad.969202","article-title":"E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1\/mSin3B corepressor complex.","volume":"16","author":"Rayman","year":"2002","journal-title":"Genes Dev."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies.","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.devcel.2018.11.042","article-title":"Tracing the origins of axolotl limb regeneration.","volume":"47","author":"Rivera-Gonzalez","year":"2018","journal-title":"Dev. Cell"},{"key":"B50","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.ydbio.2012.03.022","article-title":"Nerve signaling regulates basal keratinocyte proliferation in the blastema apical epithelial cap in the axolotl (Ambystoma mexicanum).","volume":"366","author":"Satoh","year":"2012","journal-title":"Dev. Biol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.ydbio.2007.09.021","article-title":"Nerve-induced ectopic limb blastemas in the axolotl are equivalent to amputation-induced blastemas.","volume":"312","author":"Satoh","year":"2007","journal-title":"Dev. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1002\/jez.1401360207","article-title":"The effects of microquantitles of beryllium ion on the regenerating forelimb of the adult newt, triturus.","volume":"136","author":"Scheuing","year":"1957","journal-title":"J. Exp. Zool."},{"key":"B53","doi-asserted-by":"publisher","first-page":"2841","DOI":"10.1093\/bioinformatics\/btq534","article-title":"A simple and fast method to determine the parameters for fuzzy c-means cluster analysis.","volume":"26","author":"Schwammle","year":"2010","journal-title":"Bioinformatics"},{"key":"B54","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/b978-0-12-396968-2.00010-5","article-title":"Unliganded thyroid hormone receptor regulates metamorphic timing via the recruitment of histone deacetylase complexes.","volume":"105","author":"Shi","year":"2013","journal-title":"Curr. Top. Dev. Biol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"e1002936","DOI":"10.1371\/journal.pcbi.1002936","article-title":"Comparative RNA-seq analysis in the unsequenced axolotl: the oncogene burst highlights early gene expression in the blastema.","volume":"9","author":"Stewart","year":"2013","journal-title":"PLoS Comput. Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.ydbio.2005.08.021","article-title":"Nerve-dependent and -independent events in blastema formation during xenopus froglet limb regeneration.","volume":"286","author":"Suzuki","year":"2005","journal-title":"Dev. Biol."},{"key":"B57","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1016\/j.bpj.2009.06.052","article-title":"Coherent movement of cell layers during wound healing by image correlation spectroscopy.","volume":"97","author":"Tanner","year":"2009","journal-title":"Biophys. J."},{"key":"B58","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/jez.1402080111","article-title":"Regenerative responses in larval axolotl limbs with skin grafts over the amputation surface.","volume":"208","author":"Tassava","year":"1979","journal-title":"J. Exp. Zool."},{"key":"B59","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.mod.2012.08.001","article-title":"Histone deacetylases are required for amphibian tail and limb regeneration but not development.","volume":"129","author":"Taylor","year":"2012","journal-title":"Mech. Dev."},{"key":"B60","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1002\/jez.1401340209","article-title":"The effect of apical cap removal on limb regeneration in amblystoma larvae.","volume":"134","author":"Thornton","year":"1957","journal-title":"J. Exptl. Zool."},{"key":"B61","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1002\/jez.1401370108","article-title":"The inhibition of limb regeneration in urodele larvae by localized irradiation with ultraviolet light.","volume":"137","author":"Thornton","year":"1958","journal-title":"J. Exptl. Zool."},{"key":"B62","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/0012-1606(60)90054-3","article-title":"Influence of an eccentric epidermal cap on limb regeneration in amblystoma larvae.","volume":"2","author":"Thornton","year":"1960","journal-title":"Dev. Biol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"e26382","DOI":"10.1371\/journal.pone.0026382","article-title":"HDAC activity is required during xenopus tail regeneration.","volume":"6","author":"Tseng","year":"2011","journal-title":"PLoS One"},{"key":"B64","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.ydbio.2019.04.008","article-title":"FGF, BMP, and RA signaling are sufficient for the Induction of complete limb regeneration from non-regenerating wounds on ambystoma mexicanum limbs.","volume":"451","author":"Vieira","year":"2019","journal-title":"Dev. Biol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1002\/reg2.37","article-title":"Gene expression during the first 28 days of axolotl limb regeneration I: experimental design and global analysis of gene expression.","volume":"2","author":"Voss","year":"2015","journal-title":"Regeneration"},{"key":"B66","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.ydbio.2019.02.011","article-title":"Nerve-mediated expression of histone deacetylases regulates limb regeneration in axolotls.","volume":"449","author":"Wang","year":"2019","journal-title":"Dev. Biol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.mod.2017.01.005","article-title":"Chemical activation of Wnt\/\u03b2-catenin signalling inhibits innervation and causes skeletal tissue malformations during axolotl limb regeneration.","volume":"144","author":"Wischin","year":"2017","journal-title":"Mech. Dev."},{"key":"B68","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1186\/1471-2164-14-434","article-title":"De novo transcriptome sequencing of axolotl blastema for identification of differentially expressed genes during limb regeneration.","volume":"14","author":"Wu","year":"2013","journal-title":"BMC Genom."},{"key":"B69","doi-asserted-by":"publisher","first-page":"e21721","DOI":"10.1371\/journal.pone.0021721","article-title":"Different requirement for Wnt\/\u03b2-catenin signaling in limb regeneration of larval and adult Xenopus.","volume":"6","author":"Yokoyama","year":"2011","journal-title":"PLoS One"},{"key":"B70","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: an R package for comparing biological themes among gene clusters.","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B71","doi-asserted-by":"publisher","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 somatic chondrogenesis.","volume":"16","author":"Zeng","year":"2002","journal-title":"Genes Dev."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.641987\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T08:10:23Z","timestamp":1620634223000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.641987\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,10]]},"references-count":71,"alternative-id":["10.3389\/fcell.2021.641987"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.641987","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,10]]},"article-number":"641987"}}