{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:06:34Z","timestamp":1785215194724,"version":"3.55.0"},"reference-count":85,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Fund at Memorial University (Curtis French)"},{"name":"Atlantic Canada Opportunities Agency\u2014Community Innovation Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Bone diseases such as otosclerosis (conductive hearing loss) and osteoporosis (low bone mineral density) can result from the abnormal expression of genes that regulate cartilage and bone development. The forkhead box transcription factor FOXL1 has been identified as the causative gene in a family with autosomal dominant otosclerosis and has been reported as a candidate gene in GWAS meta-analyses for osteoporosis. This potentially indicates a novel role for foxl1 in chondrogenesis, osteogenesis, and bone remodelling. We created a foxl1 mutant zebrafish strain as a model for otosclerosis and osteoporosis and examined jaw bones that are homologous to the mammalian middle ear bones, and mineralization of the axial skeleton. We demonstrate that foxl1 regulates the expression of collagen genes such as collagen type 1 alpha 1a and collagen type 11 alpha 2, and results in a delay in jawbone mineralization, while the axial skeleton remains unchanged. foxl1 may also act with other forkhead genes such as foxc1a, as loss of foxl1 in a foxc1a mutant background increases the severity of jaw calcification phenotypes when compared to each mutant alone. Our zebrafish model demonstrates atypical cartilage formation and mineralization in the zebrafish craniofacial skeleton in foxl1 mutants and demonstrates that aberrant collagen expression may underlie the development of otosclerosis.<\/jats:p>","DOI":"10.3390\/genes13071107","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T21:55:19Z","timestamp":1655848519000},"page":"1107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mutation of foxl1 Results in Reduced Cartilage Markers in a Zebrafish Model of Otosclerosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Alexia","family":"Hawkey-Noble","sequence":"first","affiliation":[{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin A.","family":"Pater","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6394-1647","authenticated-orcid":false,"given":"Roshni","family":"Kollipara","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meriel","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre S.","family":"Maekawa","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5219-9993","authenticated-orcid":false,"given":"Christopher S.","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4673-6470","authenticated-orcid":false,"given":"Terry-Lynn","family":"Young","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis R.","family":"French","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bone.2015.04.035","article-title":"Bone Development","volume":"80","author":"Berendsen","year":"2015","journal-title":"Bone"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1242\/dev.118950","article-title":"Building the Backbone: The Development and Evolution of Vertebral Patterning","volume":"142","author":"Fleming","year":"2015","journal-title":"Development"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0091-679X(04)76018-5","article-title":"Development of Cartilage and Bone","volume":"Volume 76","author":"Javidan","year":"2004","journal-title":"Methods in Cell Biology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1242\/dev.105536","article-title":"A Pathway to Bone: Signaling Molecules and Transcription Factors Involved in Chondrocyte Development and Maturation","volume":"142","author":"Kozhemyakina","year":"2015","journal-title":"Development"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115409","DOI":"10.1016\/j.bone.2020.115409","article-title":"The Development, Patterning and Evolution of Neural Crest Cell Differentiation into Cartilage and Bone","volume":"137","author":"Dash","year":"2020","journal-title":"Bone"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1101\/gad.11.7.926","article-title":"The Winged Helix Transcription Factor MFH1 Is Required for Proliferation and Patterning of Paraxial Mesoderm in the Mouse Embryo","volume":"11","author":"Winnier","year":"1997","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/bs.ctdb.2019.01.007","article-title":"Roles and Regulation of SOX Transcription Factors in Skeletogenesis","volume":"133","author":"Lefebvre","year":"2019","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"a008334","DOI":"10.1101\/cshperspect.a008334","article-title":"Development of the Endochondral Skeleton","volume":"5","author":"Long","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Abe, Y., Tanaka, N., Abe, Y., and Tanaka, N. (2017). Roles of the Hedgehog Signaling Pathway in Epidermal and Hair Follicle Development, Homeostasis, and Cancer. J. Dev. Biol., 5.","DOI":"10.3390\/jdb5040012"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/S0960-9822(00)80052-4","article-title":"Inhibition of Sonic Hedgehog Signaling in Vivo Results in Craniofacial Neural Crest Cell Death","volume":"9","author":"Ahlgren","year":"1999","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1242\/dev.143792","article-title":"Shh Promotes Direct Interactions between Epidermal Cells and Osteoblast Progenitors to Shape Regenerated Zebrafish Bone","volume":"144","author":"Armstrong","year":"2017","journal-title":"Development"},{"key":"ref_12","unstructured":"Avaron, F., Smith, A., and Akimenko, M.-A. (2013). Sonic Hedgehog Signaling in the Developing and Regenerating Fins of Zebrafish, Landes Bioscience."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12964-018-0220-7","article-title":"de S. e A Highlight on Sonic Hedgehog Pathway","volume":"16","author":"Carballo","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1172\/JCI11706","article-title":"Indian Hedgehog Couples Chondrogenesis to Osteogenesis in Endochondral Bone Development","volume":"107","author":"Chung","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1242\/dev.02281","article-title":"Early Hedgehog Signaling from Neural to Oral Epithelium Organizes Anterior Craniofacial Development","volume":"133","author":"Eberhart","year":"2006","journal-title":"Development"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s12015-007-0006-6","article-title":"Networking of WNT, FGF, Notch, BMP, and Hedgehog Signaling Pathways during Carcinogenesis","volume":"3","author":"Katoh","year":"2007","journal-title":"Stem Cell Rev. Totowa"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/dvdy.20430","article-title":"Foxc1 Integrates Fgf and Bmp Signalling Independently of Twist or Noggin during Calvarial Bone Development","volume":"233","author":"Rice","year":"2005","journal-title":"Dev. Dyn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.ajhg.2012.02.026","article-title":"Attenuated BMP1 Function Compromises Osteogenesis, Leading to Bone Fragility in Humans and Zebrafish","volume":"90","author":"Asharani","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","first-page":"1411","article-title":"Transcriptional Regulation of WNT2B Based on the Balance of Hedgehog, Notch, BMP and WNT Signals","volume":"34","author":"Katoh","year":"2009","journal-title":"Int. J. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.bbrc.2004.11.067","article-title":"BMP Signaling in Skeletal Development","volume":"328","author":"Wan","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chrystal, P.W., French, C.R., Jean, F., Havrylov, S., van Baarle, S., Peturson, A.-M., Xu, P., Crump, J.G., Pilgrim, D.B., and Lehmann, O.J. (2021). The Axenfeld-Rieger Syndrome Gene FOXC1 Contributes to Left-Right Patterning. Genes, 12.","DOI":"10.3390\/genes12020170"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.bbrc.2009.06.071","article-title":"The Forkhead Transcription Factor Foxc2 Stimulates Osteoblast Differentiation","volume":"386","author":"Kim","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1101\/gad.907301","article-title":"The Murine Winged Helix Transcription Factors, Foxc1 and Foxc2, Are Both Required for Cardiovascular Development and Somitogenesis","volume":"15","author":"Kume","year":"2001","journal-title":"Genes Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e63595","DOI":"10.7554\/eLife.63595","article-title":"Foxc1 Establishes Enhancer Accessibility for Craniofacial Cartilage Differentiation","volume":"10","author":"Xu","year":"2021","journal-title":"eLife"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"dev.165498","DOI":"10.1242\/dev.165498","article-title":"Fox Proteins Are Modular Competency Factors for Facial Cartilage and Tooth Specification","volume":"145","author":"Xu","year":"2018","journal-title":"Development"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"You, W., Gao, H., Fan, L., Duan, D., Wang, C., and Wang, K. (2013). Foxc2 Regulates Osteogenesis and Angiogenesis of Bone Marrow Mesenchymal Stem Cells. BMC Musculoskelet. Disord., 14.","DOI":"10.1186\/1471-2474-14-199"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10235","DOI":"10.1093\/nar\/gkab807","article-title":"Toward a Mechanistic Understanding of DNA Binding by Forkhead Transcription Factors and Its Perturbation by Pathogenic Mutations","volume":"49","author":"Dai","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/nrg2523","article-title":"The Evolution of Fox Genes and Their Role in Development and Disease","volume":"10","author":"Hannenhalli","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1359\/jbmr.2001.16.10.1765","article-title":"Bone Morphogenetic Protein Regulation of Forkhead\/Winged Helix Transcription Factor Foxc2 (Mfh1) in a Murine Mesodermal Cell Line C1 and in Skeletal Precursor Cells","volume":"16","author":"Nifuji","year":"2001","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"ref_30","first-page":"1034","article-title":"Foxc1 Controls the Growth of the Murine Frontal Bone Rudiment by Direct Regulation of a Bmp Response Threshold of Msx2","volume":"140","author":"Sun","year":"2013","journal-title":"Dev. Camb. Engl."},{"key":"ref_31","first-page":"188","article-title":"Danio Rerio: The Janus of the Bone from Embryo to Scale","volume":"12","author":"Mariotti","year":"2015","journal-title":"Clin. Cases Miner. Bone Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1038\/ejhg.2009.93","article-title":"Axenfeld\u2013Rieger Syndrome and Spectrum of PITX2 and FOXC1 Mutations","volume":"17","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wang, R., Wang, W.-Q., Li, X.-Q., Zhao, J., Yang, K., Feng, Y., Guo, M.-M., Liu, M., Liu, X., and Wang, X. (2021). A Novel Variant in FOXC1 Associated with Atypical Axenfeld-Rieger Syndrome. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-01130-7"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"French, C.R. (2021). Mechanistic Insights into Axenfeld-Rieger Syndrome from Zebrafish Foxc1 and Pitx2 Mutants. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810001"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00439-021-02381-1","article-title":"A Pathogenic Deletion in Forkhead Box L1 (FOXL1) Identifies the First Otosclerosis (OTSC) Gene","volume":"141","author":"Abdelfatah","year":"2021","journal-title":"Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"233","DOI":"10.11005\/jbm.2016.23.4.233","article-title":"Replication of Caucasian Loci Associated with Osteoporosis-Related Traits in East Asians","volume":"23","author":"Kim","year":"2016","journal-title":"J. Bone Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S376","DOI":"10.1016\/j.bone.2010.09.058","article-title":"Novel Genetic Loci Associated with Osteoporosis","volume":"47","author":"Kung","year":"2010","journal-title":"Bone"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"99","DOI":"10.11005\/jbm.2014.21.2.99","article-title":"Genome-Wide Association Studies for Osteoporosis: A 2013 Update","volume":"21","author":"Liu","year":"2014","journal-title":"J. Bone Metab."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"the Genetic Factors for Osteoporosis (GEFOS) Consortium, Rivadeneira, F., Styrk\u00e1rsdottir, U., Estrada, K., Halld\u00f3rsson, B.V., Hsu, Y.-H., Richards, J.B., Zillikens, M.C., Kavvoura, F.K., and Amin, N. (2009). Twenty Bone-Mineral-Density Loci Identified by Large-Scale Meta-Analysis of Genome-Wide Association Studies. Nat. Genet., 41, 1199\u20131206.","DOI":"10.1038\/ng.446"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.jcmgh.2015.12.004","article-title":"Foxl1-Expressing Mesenchymal Cells Constitute the Intestinal Stem Cell Niche","volume":"2","author":"Aoki","year":"2016","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5936","DOI":"10.1074\/jbc.M808103200","article-title":"FoxF1 and FoxL1 Link Hedgehog Signaling and the Control of Epithelial Proliferation in the Developing Stomach and Intestine","volume":"284","author":"Madison","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.visres.2019.01.008","article-title":"Loss of Foxc1 in Zebrafish Reduces Optic Nerve Size and Cell Number in the Retinal Ganglion Cell Layer","volume":"156","author":"Umali","year":"2019","journal-title":"Vision Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ydbio.2019.06.005","article-title":"Foxc1 Is Required for Embryonic Head Vascular Smooth Muscle Differentiation in Zebrafish","volume":"453","author":"Whitesell","year":"2019","journal-title":"Dev. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/bonekey.2013.179","article-title":"A Bone to Pick with Zebrafish","volume":"2","author":"Mackay","year":"2013","journal-title":"BoneKEy Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/bs.mcb.2016.09.001","article-title":"Chapter 13\u2014Small Teleost Fish Provide New Insights into Human Skeletal Diseases","volume":"Volume 138","author":"Detrich","year":"2017","journal-title":"Methods in Cell Biology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0925-4773(96)00625-9","article-title":"Conservation of BMP Signaling in Zebrafish Mesoderm Patterning","volume":"61","author":"Nikaido","year":"1997","journal-title":"Mech. Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.1242\/dev.01943","article-title":"Hedgehog Signaling Is Required for Cranial Neural Crest Morphogenesis and Chondrogenesis at the Midline in the Zebrafish Skull","volume":"132","author":"Wada","year":"2005","journal-title":"Development"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.3389\/fcell.2020.600926","article-title":"Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors","volume":"8","author":"Raterman","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/bs.ctdb.2015.07.001","article-title":"Zebrafish Craniofacial Development: A Window into Early Patterning","volume":"115","author":"Mork","year":"2015","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fendo.2019.00006","article-title":"Zebrafish as an Emerging Model for Osteoporosis: A Primary Testing Platform for Screening New Osteo-Active Compounds","volume":"10","author":"Bergen","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1469-7580.2012.01526.x","article-title":"Evolution of the Mammalian Middle Ear and Jaw: Adaptations and Novel Structures","volume":"222","author":"Anthwal","year":"2013","journal-title":"J. Anat."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1002\/jez.b.21347","article-title":"History of Studies on Mammalian Middle Ear Evolution: A Comparative Morphological and Developmental Biology Perspective","volume":"314B","author":"Takechi","year":"2010","journal-title":"J. Exp. Zoolog. B Mol. Dev. Evol."},{"key":"ref_53","first-page":"1410","article-title":"Uncovering the Secreted Signals and Transcription Factors Regulating the Development of Mammalian Middle Ear Ossicles","volume":"249","author":"Ankamreddy","year":"2020","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/B978-0-12-381320-6.00010-2","article-title":"Chapter 10\u2014Not All Bones Are Created Equal\u2014Using Zebrafish and Other Teleost Species in Osteogenesis Research","volume":"Volume 105","author":"Detrich","year":"2011","journal-title":"Methods in Cell Biology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jmbbm.2018.05.004","article-title":"Zebrafish as a Model to Study Bone Maturation: Nanoscale Structural and Mechanical Characterization of Age-Related Changes in the Zebrafish Vertebral Column","volume":"84","author":"Chang","year":"2018","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1006\/dbio.2001.0390","article-title":"Visualizing Normal and Defective Bone Development in Zebrafish Embryos Using the Fluorescent Chromophore Calcein","volume":"238","author":"Du","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/ame2.12000","article-title":"Application of Bone Transgenic Zebrafish in Anti-Osteoporosis Chemical Screening","volume":"1","author":"Huang","year":"2018","journal-title":"Anim. Models Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.bone.2019.02.009","article-title":"Using Zebrafish to Study Skeletal Genomics","volume":"126","author":"Kwon","year":"2019","journal-title":"Bone"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/aja.1002030302","article-title":"Stages of Embryonic Development of the Zebrafish","volume":"203","author":"Kimmel","year":"1995","journal-title":"Dev. Dyn."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1080\/10520290701333558","article-title":"A Two-Color Acid-Free Cartilage and Bone Stain for Zebrafish Larvae","volume":"82","author":"Walker","year":"2007","journal-title":"Biotech. Histochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nprot.2007.514","article-title":"High-Resolution in Situ Hybridization to Whole-Mount Zebrafish Embryos","volume":"3","author":"Thisse","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_62","first-page":"1470","article-title":"RNA Isolation from Embryonic Zebrafish and CDNA Synthesis for Gene Expression Analysis","volume":"30","author":"Peterson","year":"2009","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_64","first-page":"71","article-title":"An Improvement of the 2\u02c6 (\u2013Delta Delta CT) Method for Quantitative Real-Time Polymerase Chain Reaction Data Analysis","volume":"3","author":"Rao","year":"2013","journal-title":"Biostat. Bioinforma. Biomath."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.anl.2015.11.001","article-title":"Relation of Otosclerosis and Osteoporosis: A Bone Mineral Density Study","volume":"43","author":"Atan","year":"2016","journal-title":"Auris. Nasus. Larynx"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00405-008-0790-x","article-title":"An Overview of the Etiology of Otosclerosis","volume":"266","author":"Markou","year":"2008","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1159\/000057789","article-title":"Etiopathogenesis of Otosclerosis","volume":"64","author":"Niedermeyer","year":"2002","journal-title":"ORL"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/ajmg.a.35276","article-title":"COL1A1 Association and Otosclerosis: A Meta-Analysis","volume":"158A","author":"Schrauwen","year":"2012","journal-title":"Am. J. Med. Genet. A."},{"key":"ref_69","first-page":"45","article-title":"Expression of Collagens in the Otosclerotic Bone","volume":"65","author":"Niedermeyer","year":"2007","journal-title":"Adv. Otorhinolaryngol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.ydbio.2009.07.025","article-title":"A Gain of Function Mutation Causing Skeletal Overgrowth in the Rapunzel Mutant","volume":"334","author":"Green","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.ydbio.2015.04.007","article-title":"Distinct Effects of Hoxa2 Overexpression in Cranial Neural Crest Populations Reveal That the Mammalian Hyomandibular-Ceratohyal Boundary Maps within the Styloid Process","volume":"402","author":"Kitazawa","year":"2015","journal-title":"Dev. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"7246","DOI":"10.1128\/MCB.00429-06","article-title":"Transcriptional Repressor Foxl1 Regulates Central Nervous System Development by Suppressing Shh Expression in Zebra Fish","volume":"26","author":"Nakada","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41586-019-1064-z","article-title":"Genetic Compensation Triggered by Mutant MRNA Degradation","volume":"568","author":"Kontarakis","year":"2019","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"El-Brolosy, M.A., and Stainier, D.Y.R. (2017). Genetic Compensation: A Phenomenon in Search of Mechanisms. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006780"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Salanga, C.M., and Salanga, M.C. (2021). Genotype to Phenotype: CRISPR Gene Editing Reveals Genetic Compensation as a Mechanism for Phenotypic Disjunction of Morphants and Mutants. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073472"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1258\/0022215041917790","article-title":"Association between Osteoporosis and Otosclerosis in Women","volume":"118","author":"Clayton","year":"2004","journal-title":"J. Laryngol. Otol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7302","DOI":"10.1128\/MCB.00758-07","article-title":"The Forkhead Factor FoxE1 Binds to the Thyroperoxidase Promoter during Thyroid Cell Differentiation and Modifies Compacted Chromatin Structure","volume":"27","author":"Cuesta","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1101\/gad.1775509","article-title":"Nucleosome-Binding Affinity as a Primary Determinant of the Nuclear Mobility of the Pioneer Transcription Factor FoxA","volume":"23","author":"Sekiya","year":"2009","journal-title":"Genes Dev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1111\/cge.13148","article-title":"Axenfeld-Rieger Syndrome","volume":"93","author":"Seifi","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0009-8981(01)00586-1","article-title":"Hemopexin: A Review of Biological Aspects and the Role in Laboratory Medicine","volume":"312","author":"Delanghe","year":"2001","journal-title":"Clin. Chim. Acta"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1089\/104454902753759717","article-title":"Hemopexin: Structure, Function, and Regulation","volume":"21","author":"Tolosano","year":"2002","journal-title":"DNA Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"dev181040","DOI":"10.1242\/dev.181040","article-title":"Dual Role of Jam3b in Early Hematopoietic and Vascular Development","volume":"147","author":"Kobayashi","year":"2020","journal-title":"Development"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1007\/s00198-004-1739-6","article-title":"Bone Density and Hemoglobin Levels in Older Persons: Results from the InCHIANTI Study","volume":"16","author":"Cesari","year":"2005","journal-title":"Osteoporos. Int. J. Establ. Result Coop. Eur. Found. Osteoporos. Natl. Osteoporos. Found. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1557988319850378","DOI":"10.1177\/1557988319850378","article-title":"Low Hemoglobin Is Associated with Low Bone Mineral Density and High Risk of Bone Fracture in Male Adults: A Retrospective Medical Record Review Study","volume":"13","author":"Chuang","year":"2019","journal-title":"Am. J. Mens Health"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1002\/jbmr.3026","article-title":"Bone Health in Patients with Hematopoietic Disorders of Bone Marrow Origin: Systematic Review and Meta-Analysis","volume":"32","author":"Steer","year":"2017","journal-title":"J. Bone Miner. Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1107\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:36:25Z","timestamp":1760139385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,21]]},"references-count":85,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["genes13071107"],"URL":"https:\/\/doi.org\/10.3390\/genes13071107","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,21]]}}}