{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:36:02Z","timestamp":1768505762907,"version":"3.49.0"},"posted":{"date-parts":[[2023,4,4]]},"group-title":"Developmental Biology","reference-count":72,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,4,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Taste papillae are specialized organs each of which is comprised of an epithelial wall hosting taste buds and a core of mesenchymal tissue. In the present study, we report that during the early stages of embryonic development, bone morphogenetic protein (BMP) signaling mediated by type 1 receptor ALK3 in the tongue mesenchyme is required for the epithelial Wnt\/\u03b2-catenin activity and taste papilla cell differentiation. Mesenchyme-specific knockout (\n                  <jats:italic>cKO<\/jats:italic>\n                  ) of\n                  <jats:italic>Alk3<\/jats:italic>\n                  using\n                  <jats:italic>Wnt1-Cre<\/jats:italic>\n                  and\n                  <jats:italic>Sox10-Cre<\/jats:italic>\n                  resulted in an absence of taste papillae at E12.0. Biochemical and cell differentiation analyses demonstrated that mesenchymal ALK3-BMP signaling governs the production of previously unappreciated secretory proteins, i.e., suppresses those that inhibiting and facilitates those promoting taste cell differentiation. Bulk RNA-Sequencing analysis revealed many more differentially expressed genes (DEGs) in the tongue epithelium than in the mesenchyme in\n                  <jats:italic>Alk3 cKO<\/jats:italic>\n                  vs control. Moreover, we detected a down-regulated epithelial Wnt\/\u03b2-catenin signaling, and taste papilla development in the\n                  <jats:italic>Alk3 cKO<\/jats:italic>\n                  was rescued by GSK3\u03b2 inhibitor LiCl, but not Wnt3a. Our findings demonstrate for the first time the requirement of tongue mesenchyme in taste papilla cell differentiation.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary statement<\/jats:title>\n                  <jats:p>This is the first set of data to implicate the requirement of tongue mesenchyme in taste papilla cell differentiation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.04.03.535414","type":"posted-content","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T14:05:13Z","timestamp":1680617113000},"source":"Crossref","is-referenced-by-count":0,"title":["Taste papilla cell differentiation requires tongue mesenchyme via ALK3-BMP signaling to regulate the production of secretory proteins"],"prefix":"10.64898","author":[{"given":"Mohamed","family":"Ishan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhonghou","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Stice","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lance","family":"Wells","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Mishina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5515-9869","authenticated-orcid":false,"given":"Hong-Xiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023040605500856000_2023.04.03.535414v1.1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.120394"},{"key":"2023040605500856000_2023.04.03.535414v1.2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.030544"},{"key":"2023040605500856000_2023.04.03.535414v1.3","doi-asserted-by":"crossref","unstructured":"Bernatik, O. , Radaszkiewicz, T. , Behal, M. , Dave, Z. , Witte, F. , Mahl, A. , Cernohorsky, N. H. , Krejci, P. , Stricker, S. & Bryja, V . 2017. A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a\/Ror2\/Disheveled Pathway Activation. Frontiers in Cell and Developmental Biology, 5.","DOI":"10.3389\/fcell.2017.00047"},{"key":"2023040605500856000_2023.04.03.535414v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2010.10.003"},{"key":"2023040605500856000_2023.04.03.535414v1.5","doi-asserted-by":"publisher","DOI":"10.1242\/dev.150342"},{"key":"2023040605500856000_2023.04.03.535414v1.6","doi-asserted-by":"publisher","DOI":"10.1242\/dev.107631"},{"key":"2023040605500856000_2023.04.03.535414v1.7","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-012110-142225"},{"key":"2023040605500856000_2023.04.03.535414v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/PL00000650"},{"key":"2023040605500856000_2023.04.03.535414v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505259102"},{"key":"2023040605500856000_2023.04.03.535414v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/BF02096300"},{"key":"2023040605500856000_2023.04.03.535414v1.11","doi-asserted-by":"publisher","DOI":"10.1177\/10454411910020010101"},{"key":"2023040605500856000_2023.04.03.535414v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2023040605500856000_2023.04.03.535414v1.13","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903040203"},{"key":"2023040605500856000_2023.04.03.535414v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20731"},{"key":"2023040605500856000_2023.04.03.535414v1.15","doi-asserted-by":"crossref","first-page":"e1006990","DOI":"10.1371\/journal.pgen.1006990","article-title":"\u03b2-catenin is required for taste bud cell renewal and behavioral taste perception in adult mice","volume":"13","year":"2017","journal-title":"PLoS genetics"},{"key":"2023040605500856000_2023.04.03.535414v1.16","doi-asserted-by":"crossref","first-page":"e1005208","DOI":"10.1371\/journal.pgen.1005208","article-title":"\u03b2-Catenin Signaling Biases Multipotent Lingual Epithelial Progenitors to Differentiate and Acquire Specific Taste Cell Fates","volume":"11","year":"2015","journal-title":"PLOS Genetics"},{"key":"2023040605500856000_2023.04.03.535414v1.17","doi-asserted-by":"publisher","DOI":"10.1242\/dev.076653"},{"key":"2023040605500856000_2023.04.03.535414v1.18","doi-asserted-by":"publisher","DOI":"10.1055\/s-2006-957332"},{"key":"2023040605500856000_2023.04.03.535414v1.19","doi-asserted-by":"crossref","first-page":"e23337","DOI":"10.1002\/dvg.23337","article-title":"Increased activity of mesenchymal ALK2-BMP signaling causes posteriorly truncated microglossia and disorganization of lingual tissues","volume":"58","year":"2020","journal-title":"genesis"},{"key":"2023040605500856000_2023.04.03.535414v1.20","doi-asserted-by":"crossref","first-page":"e13144","DOI":"10.1111\/cpr.13144","article-title":"Deletion of Nf2 in neural crest-derived tongue mesenchyme alters tongue shape and size, Hippo signalling and cell proliferation in a region-and stage-specific manner","volume":"54","year":"2021","journal-title":"Cell Prolif"},{"key":"2023040605500856000_2023.04.03.535414v1.21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607399104"},{"key":"2023040605500856000_2023.04.03.535414v1.22","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1089\/ten.teb.2014.0678","article-title":"Epithelial\u2013Mesenchymal Interactions in Urinary Bladder and Small Intestine and How to Apply Them in Tissue Engineering","volume":"21","year":"2015","journal-title":"Tissue Engineering Part B: Reviews"},{"key":"2023040605500856000_2023.04.03.535414v1.23","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.8.1607"},{"key":"2023040605500856000_2023.04.03.535414v1.24","unstructured":"Kaufman, M. H. 1992. The Atlas of Mouse Development 1st Edition. 512."},{"key":"2023040605500856000_2023.04.03.535414v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2011.11.014"},{"key":"2023040605500856000_2023.04.03.535414v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1857"},{"key":"2023040605500856000_2023.04.03.535414v1.27","doi-asserted-by":"publisher","DOI":"10.4161\/org.4.2.5851"},{"key":"2023040605500856000_2023.04.03.535414v1.28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.bbrc.2019.05.132","article-title":"Early taste buds are from Shh+ epithelial cells of tongue primordium in distinction from mature taste bud cells which arise from surrounding tissue compartments","volume":"515","year":"2019","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"2023040605500856000_2023.04.03.535414v1.29","doi-asserted-by":"crossref","unstructured":"Krimm, R. F. , Thirumangalathu, S. & Barlow, L. A . 2015. Development of the taste system. Handbook of Olfaction and Gustation, 727\u2013748.","DOI":"10.1002\/9781118971758.ch33"},{"key":"2023040605500856000_2023.04.03.535414v1.30","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1471-213X-11-43","article-title":"Two-color fluorescent in situ hybridization in the embryonic zebrafish brain using differential detection systems","volume":"11","year":"2011","journal-title":"BMC Developmental Biology"},{"key":"2023040605500856000_2023.04.03.535414v1.31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.025478"},{"key":"2023040605500856000_2023.04.03.535414v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/ng1932"},{"key":"2023040605500856000_2023.04.03.535414v1.33","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1002\/dvdy.21657","article-title":"Fungiform papilla pattern: EGF regulates inter-papilla lingual epithelium and decreases papilla number by means of PI3K\/Akt, MEK\/Erk, and p38 MAPK signaling","volume":"237","year":"2008","journal-title":"Developmental dynamics : an official publication of the American Association of Anatomists"},{"key":"2023040605500856000_2023.04.03.535414v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2012.05.028"},{"key":"2023040605500856000_2023.04.03.535414v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.07.042"},{"key":"2023040605500856000_2023.04.03.535414v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2013.07.022"},{"key":"2023040605500856000_2023.04.03.535414v1.37","doi-asserted-by":"crossref","first-page":"e23093","DOI":"10.1002\/dvg.23093","article-title":"Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death","volume":"56","year":"2018","journal-title":"Genesis"},{"key":"2023040605500856000_2023.04.03.535414v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.7"},{"key":"2023040605500856000_2023.04.03.535414v1.39","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2023040605500856000_2023.04.03.535414v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2009.06.016"},{"key":"2023040605500856000_2023.04.03.535414v1.41","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1350705"},{"key":"2023040605500856000_2023.04.03.535414v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/nature03837"},{"key":"2023040605500856000_2023.04.03.535414v1.43","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19970120)377:3<324::AID-CNE2>3.0.CO;2-4"},{"key":"2023040605500856000_2023.04.03.535414v1.44","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10551"},{"key":"2023040605500856000_2023.04.03.535414v1.45","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.24.3027"},{"key":"2023040605500856000_2023.04.03.535414v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/S0012-1606(02)00014-3"},{"key":"2023040605500856000_2023.04.03.535414v1.47","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1002\/dvdy.24121","article-title":"Sonic hedgehog-expressing basal cells are general post-mitotic precursors of functional taste receptor cells","volume":"243","year":"2014","journal-title":"Developmental dynamics : an official publication of the American Association of Anatomists"},{"key":"2023040605500856000_2023.04.03.535414v1.48","doi-asserted-by":"publisher","DOI":"10.1242\/dev.038133"},{"key":"2023040605500856000_2023.04.03.535414v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81903-0"},{"key":"2023040605500856000_2023.04.03.535414v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.12.158"},{"key":"2023040605500856000_2023.04.03.535414v1.51","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2008-0611"},{"key":"2023040605500856000_2023.04.03.535414v1.52","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1985.04060090062015"},{"key":"2023040605500856000_2023.04.03.535414v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3122"},{"key":"2023040605500856000_2023.04.03.535414v1.54","doi-asserted-by":"crossref","first-page":"e1002098","DOI":"10.1371\/journal.pgen.1002098","article-title":"FGF signaling regulates the number of posterior taste papillae by controlling progenitor field size","volume":"7","year":"2011","journal-title":"PLoS genetics"},{"key":"2023040605500856000_2023.04.03.535414v1.55","doi-asserted-by":"publisher","DOI":"10.1242\/dev.148080"},{"key":"2023040605500856000_2023.04.03.535414v1.56","doi-asserted-by":"publisher","DOI":"10.1242\/dev.029926"},{"key":"2023040605500856000_2023.04.03.535414v1.57","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200420384"},{"key":"2023040605500856000_2023.04.03.535414v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604440"},{"key":"2023040605500856000_2023.04.03.535414v1.59","doi-asserted-by":"publisher","DOI":"10.4081\/oncol.2014.239"},{"key":"2023040605500856000_2023.04.03.535414v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2012.08.011"},{"key":"2023040605500856000_2023.04.03.535414v1.61","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01086"},{"key":"2023040605500856000_2023.04.03.535414v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(88)90401-0"},{"key":"2023040605500856000_2023.04.03.535414v1.63","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121012"},{"key":"2023040605500856000_2023.04.03.535414v1.64","doi-asserted-by":"publisher","DOI":"10.1242\/dev.029090"},{"key":"2023040605500856000_2023.04.03.535414v1.65","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1089\/ten.tec.2015.0377","article-title":"Taste Bud Labeling in Whole Tongue Epithelial Sheet in Adult Mice","volume":"22","year":"2016","journal-title":"Tissue Eng Part C Methods"},{"key":"2023040605500856000_2023.04.03.535414v1.66","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.gendis.2014.07.005","article-title":"Bone Morphogenetic Protein (BMP) signaling in development and human diseases","volume":"1","year":"2014","journal-title":"Genes & Diseases"},{"key":"2023040605500856000_2023.04.03.535414v1.67","doi-asserted-by":"crossref","first-page":"1807674","DOI":"10.1080\/20013078.2020.1807674","article-title":"Experimental artefacts can lead to misattribution of bioactivity from soluble mesenchymal stem cell paracrine factors to extracellular vesicles","volume":"9","year":"2020","journal-title":"Journal of Extracellular Vesicles"},{"key":"2023040605500856000_2023.04.03.535414v1.68","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200311122"},{"key":"2023040605500856000_2023.04.03.535414v1.69","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1089\/scd.2020.0022","article-title":"SOX10-Cre-Labeled Cells Under the Tongue Epithelium Serve as Progenitors for Taste Bud Cells That Are Mainly Type III and Keratin 8-Low","volume":"29","year":"2020","journal-title":"Stem Cells and Development"},{"key":"2023040605500856000_2023.04.03.535414v1.70","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.431775"},{"key":"2023040605500856000_2023.04.03.535414v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.05.022"},{"key":"2023040605500856000_2023.04.03.535414v1.72","doi-asserted-by":"publisher","DOI":"10.1177\/0022034514531985"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.04.03.535414","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:30:03Z","timestamp":1768451403000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.04.03.535414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,4]]},"references-count":72,"URL":"https:\/\/doi.org\/10.1101\/2023.04.03.535414","relation":{},"subject":[],"published":{"date-parts":[[2023,4,4]]},"subtype":"preprint"}}