{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T18:20:17Z","timestamp":1772821217811,"version":"3.50.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE029818 R01DE030122"],"award-info":[{"award-number":["R01DE029818 R01DE030122"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007270","name":"University of Michigan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007270","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Hypertelorism, characterized by an abnormal increase in the distance between the eyes, is often associated with various congenital birth defects. While there is increasing evidence suggesting common underlying mechanisms for hypertelorism, the role of microRNAs (miRNAs)\u2014short noncoding RNAs that suppress target genes by inhibiting translation and degrading mRNA\u2014in the condition\u2019s pathogenesis remains unclear. This study aimed to identify the miRNAs associated with hypertelorism in mice. By searching the Mouse Genome Informatics (MGI) database and reviewing full-text references, we identified a total of 31 genes potentially related to hypertelorism. Advanced bioinformatics analyses revealed nine miRNAs that may regulate these genes. We experimentally evaluated candidate miRNAs in assays of cell proliferation and target gene regulation in primary cells isolated from developing frontonasal process mouse embryonic frontonasal mesenchymal and O9-1 cells, a murine neural crest cell line. Our findings indicated that overexpression of either miR-383-3p or miR-6951-3p stimulated cell proliferation, whereas miR-7116-3p and miR-124-3p did not have this effect. Additionally, we confirmed that miR-383-3p and miR-6951-3p regulated the expression of a set of hypertelorism-related genes in a dose-dependent manner. These results suggest that miR-383-3p and miR-6951-3p play significant roles in the development of hypertelorism.<\/jats:p>","DOI":"10.3389\/fcell.2025.1587052","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T06:59:32Z","timestamp":1753340372000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["miR-383-3p and miR-6951-3p activate cell proliferation through the regulation of genes related to hypertelorism"],"prefix":"10.3389","volume":"13","author":[{"given":"Chihiro","family":"Iwaya","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junichi","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/s41580-021-00354-w","article-title":"MicroRNA-mediated regulation of glucose and lipid metabolism","volume":"22","author":"Agbu","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"158715","DOI":"10.1016\/j.bbalip.2020.158715","article-title":"Expression of the type 1 lysophosphatidic acid receptor in osteoblastic cell lineage controls both bone mineralization and osteocyte specification","volume":"1865","author":"Alioli","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"B3","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cmet.2012.11.001","article-title":"Circulating fibroblast growth factors as metabolic regulators--a critical appraisal","volume":"16","author":"Angelin","year":"2012","journal-title":"Cell Metab."},{"key":"B4","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/s0166-4328(01)00297-2","article-title":"Controlling the false discovery rate in behavior genetics research","volume":"125","author":"Benjamini","year":"2001","journal-title":"Behav. Brain Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"38505","DOI":"10.1074\/jbc.M112.400598","article-title":"Fibroblast growth factor (FGF) signaling during gastrulation negatively modulates the abundance of microRNAs that regulate proteins required for cell migration and embryo patterning","volume":"287","author":"Bobbs","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1172\/JCI22123","article-title":"Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer","volume":"114","author":"Boucharaba","year":"2004","journal-title":"J. Clin. Invest"},{"key":"B7","doi-asserted-by":"publisher","first-page":"71418","DOI":"10.18632\/oncotarget.10138","article-title":"miR-338-3p inhibits epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma cells","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"B8","doi-asserted-by":"publisher","first-page":"4353","DOI":"10.1172\/JCI43910","article-title":"Activation of multiple signaling pathways causes developmental defects in mice with a noonan syndrome-associated Sos1 mutation","volume":"120","author":"Chen","year":"2010","journal-title":"J. Clin. Invest"},{"key":"B9","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/s41588-018-0057-4","article-title":"Genome-wide mapping of global-to-local genetic effects on human facial shape","volume":"50","author":"Claes","year":"2018","journal-title":"Nat. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.ydbio.2009.04.021","article-title":"Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome","volume":"331","author":"Cobourne","year":"2009","journal-title":"Dev. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/s0901-5027(05)80465-5","article-title":"Hypertelorism: interorbital growth, measurements, and pathogenetic considerations","volume":"24","author":"Cohen","year":"1995","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"B12","doi-asserted-by":"publisher","first-page":"13384","DOI":"10.1073\/pnas.97.24.13384","article-title":"Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior","volume":"97","author":"Contos","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B13","doi-asserted-by":"publisher","first-page":"6551","DOI":"10.1074\/jbc.M113.533232","article-title":"Lysophosphatidic acid receptor type 1 (LPA1) plays a functional role in osteoclast differentiation and bone resorption activity","volume":"289","author":"David","year":"2014","journal-title":"J. Biol. Chem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"12555","DOI":"10.1073\/pnas.0405031101","article-title":"A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis","volume":"101","author":"Eswarakumar","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: a graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.bone.2011.04.018","article-title":"Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass","volume":"49","author":"Gennero","year":"2011","journal-title":"Bone"},{"key":"B17","doi-asserted-by":"publisher","first-page":"16395","DOI":"10.1073\/pnas.1418126111","article-title":"K-RasV14I recapitulates Noonan syndrome in mice","volume":"111","author":"Hernandez-Porras","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B18","doi-asserted-by":"publisher","first-page":"D148","DOI":"10.1093\/nar\/gkz896","article-title":"miRTarBase 2020: updates to the experimentally validated microRNA-target interaction database","volume":"48","author":"Huang","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"15222","DOI":"10.18632\/oncotarget.3835","article-title":"MiR-338-3p inhibits epithelial-mesenchymal transition in gastric cancer cells by targeting ZEB2 and MACC1\/Met\/Akt signaling","volume":"6","author":"Huang","year":"2015","journal-title":"Oncotarget"},{"key":"B20","doi-asserted-by":"publisher","first-page":"3552","DOI":"10.3390\/ijms24043552","article-title":"MicroRNAs and gene regulatory networks related to cleft lip and palate","volume":"24","author":"Iwaya","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"955486","DOI":"10.3389\/fcell.2022.955486","article-title":"MicroRNA-383: a tumor suppressor miRNA in human cancer","volume":"10","author":"Jafarzadeh","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.bbrc.2007.03.121","article-title":"Lysophosphatidic acid induces osteocyte dendrite outgrowth","volume":"357","author":"Karagiosis","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4673","DOI":"10.1038\/s41467-020-18483-9","article-title":"Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes","volume":"11","author":"Kent","year":"2020","journal-title":"Nat. Commun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.spen.2007.08.008","article-title":"Genetics of craniosynostosis","volume":"14","author":"Kimonis","year":"2007","journal-title":"Semin. Pediatr. Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1093\/hmg\/ddab334","article-title":"Genetic architecture of orbital telorism","volume":"31","author":"Knol","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.reprotox.2014.05.009","article-title":"A ciliopathy with hydrocephalus, isolated craniosynostosis, hypertelorism, and clefting caused by deletion of Kif3a","volume":"48","author":"Liu","year":"2014","journal-title":"Reprod. Toxicol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"5230","DOI":"10.1158\/0008-5472.CAN-20-1496","article-title":"Neural crest-like stem cell transcriptome analysis identifies LPAR1 in melanoma progression and therapy resistance","volume":"81","author":"Liu","year":"2021","journal-title":"Cancer Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: an R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"B29","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.semcdb.2015.09.021","article-title":"Metabolic fibroblast growth factors (FGFs): mediators of energy homeostasis","volume":"53","author":"Markan","year":"2016","journal-title":"Semin. Cell Dev. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.tibtech.2016.04.012","article-title":"Regulation of glucose metabolism - a perspective from cell bioprocessing","volume":"34","author":"Mulukutla","year":"2016","journal-title":"Trends Biotechnol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1002\/ajmg.a.61545","article-title":"Clinical versus automated assessments of morphological variants in twins with and without neurodevelopmental disorders","volume":"182","author":"Myers","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"B32","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.ydbio.2003.10.033","article-title":"Frontonasal process-specific disruption of AP-2alpha results in postnatal midfacial hypoplasia, vascular anomalies, and nasal cavity defects","volume":"267","author":"Nelson","year":"2004","journal-title":"Dev. Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e2122382119","DOI":"10.1073\/pnas.2122382119","article-title":"Autocrine FGF1 signaling promotes glucose uptake in adipocytes","volume":"119","author":"Nies","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/mps4010001","article-title":"miRNA targets: from prediction tools to experimental validation","volume":"4","author":"Riolo","year":"2020","journal-title":"Methods Protoc."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1038\/s41467-019-10617-y","article-title":"Facial recognition from DNA using face-to-DNA classifiers","volume":"10","author":"Sero","year":"2019","journal-title":"Nat. Commun."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2233","DOI":"10.3174\/ajnr.A3415","article-title":"Illustrated review of the embryology and development of the facial region, part 1: early face and lateral nasal cavities","volume":"34","author":"Som","year":"2013","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.mod.2018.02.003","article-title":"Genes and microRNAs associated with mouse cleft palate: a systematic review and bioinformatics analysis","volume":"150","author":"Suzuki","year":"","journal-title":"Mech. Dev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"15057","DOI":"10.1038\/s41598-018-32888-z","article-title":"The role of acetyltransferases for the temporal-specific accessibility of beta-catenin to the myogenic gene locus","volume":"8","author":"Suzuki","year":"","journal-title":"Sci. Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"dev168351","DOI":"10.1242\/dev.168351","article-title":"WNT\/\u03b2-catenin signaling plays a crucial role in myoblast fusion through regulation of Nephrin expression during development","volume":"145","author":"Suzuki","year":"","journal-title":"Development"},{"key":"B40","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1002\/dvdy.24368","article-title":"Molecular mechanisms of midfacial developmental defects","volume":"245","author":"Suzuki","year":"2016","journal-title":"Dev. Dyn."},{"key":"B41","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1186\/s12864-019-6238-4","article-title":"MicroRNA-124-3p suppresses mouse lip mesenchymal cell proliferation through the regulation of genes associated with cleft lip in the mouse","volume":"20","author":"Suzuki","year":"2019","journal-title":"BMC Genomics"},{"key":"B42","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1093\/oxfordjournals.jhered.a022981","article-title":"Mesenchymal dysplasia: a recessive mutation on chromosome 13 of the mouse","volume":"87","author":"Sweet","year":"1996","journal-title":"J. Hered."},{"key":"B43","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/nrc2780","article-title":"Fibroblast growth factor signalling: from development to cancer","volume":"10","author":"Turner","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"B44","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41588-020-00741-7","article-title":"Insights into the genetic architecture of the human face","volume":"53","author":"White","year":"2021","journal-title":"Nat. Genet."},{"key":"B45","doi-asserted-by":"publisher","first-page":"106335","DOI":"10.1016\/j.prostaglandins.2019.106335","article-title":"Lysophosphatidic acid: its role in bone cell biology and potential for use in bone regeneration","volume":"143","author":"Wu","year":"2019","journal-title":"Prostagl. Other Lipid Mediat"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e49898","DOI":"10.7554\/eLife.49898","article-title":"Novel genetic loci affecting facial shape variation in humans","volume":"8","author":"Xiong","year":"2019","journal-title":"Elife"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1177\/00220345221105816","article-title":"Spatiotemporal MicroRNA-Gene expression network related to orofacial clefts","volume":"101","author":"Yan","year":"2022","journal-title":"J. Dent. Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e23205","DOI":"10.1002\/jbt.23205","article-title":"Overexpression of miR-383-3p protects cardiomyocytes against hypoxia\/reoxygenation injury via regulating PTEN\/PI3K\/AKT signal pathway","volume":"36","author":"Zeng","year":"2022","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B49","first-page":"997","article-title":"MicroRNA-338-3p suppresses cell proliferation, migration and invasion in human malignant melanoma by targeting MACC1","volume":"18","author":"Zhang","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1093\/hmg\/9.13.2001","article-title":"A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures","volume":"9","author":"Zhou","year":"2000","journal-title":"Hum. Mol. Genet."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1587052\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T06:59:34Z","timestamp":1753340374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1587052\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,24]]},"references-count":50,"alternative-id":["10.3389\/fcell.2025.1587052"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2025.1587052","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,24]]},"article-number":"1587052"}}