{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T07:18:53Z","timestamp":1790493533018,"version":"4.1.0"},"reference-count":49,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":2329,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recent studies revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the mechanisms underlying the disease were discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S-\/-), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S-\/- and Ltbp4 null (Ltbp4-\/-) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival with distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a novel interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for ECM incorporation of fibulin-4. Overall, our results contribute to the current understanding of elastogenesis and provide of an animal model of ARCL1C.<\/jats:p>","DOI":"10.1242\/dmm.018960","type":"journal-article","created":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T07:38:55Z","timestamp":1424936335000},"source":"Crossref","is-referenced-by-count":27,"title":["Modeling autosomal recessive cutis laxa type 1C (ARCL1C) in mice reveals distinct functions of Ltbp-4 isoforms"],"prefix":"10.1242","author":[{"given":"Insa","family":"Bultmann-Mellin","sequence":"first","affiliation":[{"name":"Center for Experimental Medicine, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Conradi","sequence":"additional","affiliation":[{"name":"Center for Experimental Medicine, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra C.","family":"Maul","sequence":"additional","affiliation":[{"name":"Center for Experimental Medicine, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Dinger","sequence":"additional","affiliation":[{"name":"Center for Experimental Medicine, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Wempe","sequence":"additional","affiliation":[{"name":"Dept. of Molecular Hematology, University of Frankfurt Medical School, Frankfurt am Main, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander P.","family":"Wohl","sequence":"additional","affiliation":[{"name":"Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Imhof","sequence":"additional","affiliation":[{"name":"Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. Thomas","family":"Wunderlich","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Metabolism Research, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander C.","family":"Bunck","sequence":"additional","affiliation":[{"name":"Department of Radiology, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kansai Medical University, Osaka, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katri","family":"Koli","sequence":"additional","affiliation":[{"name":"Res. Programs Unit & Transplantation Laboratory, Haartman Inst., Uni. of Helsinki, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelm","family":"Bloch","sequence":"additional","affiliation":[{"name":"Institute of Cardiology and Sports Medicine, German Sport University Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Ghanem","sequence":"additional","affiliation":[{"name":"Department of Medicine\/Cardiology, University of Bonn, Bonn, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Heinz","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"von Melchner","sequence":"additional","affiliation":[{"name":"Dept. of Molecular Hematology, University of Frankfurt Medical School, Frankfurt am Main, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Sengle","sequence":"additional","affiliation":[{"name":"Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Sterner-Kock","sequence":"additional","affiliation":[{"name":"Center for Experimental Medicine, Medical Faculty, University of Cologne, Cologne, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2015,1,1]]},"reference":[{"key":"2021042501193401200_b1-0080403","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1006\/abio.1994.1042","article-title":"An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct","volume":"216","author":"Abe","year":"1994","journal-title":"Anal. Biochem."},{"key":"2021042501193401200_b2-0080403","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ab.2003.11.029","article-title":"A genetic screen to identify latent transforming growth factor beta activators","volume":"327","author":"Annes","year":"2004","journal-title":"Anal. Biochem."},{"issue":"Suppl. 1","key":"2021042501193401200_b3-0080403","doi-asserted-by":"crossref","first-page":"i14","DOI":"10.1136\/hrt.2005.081547","article-title":"Acquired right ventricular dysfunction","volume":"92","author":"Bleeker","year":"2006","journal-title":"Heart"},{"key":"2021042501193401200_b4-0080403","doi-asserted-by":"crossref","first-page":"e65614","DOI":"10.1371\/journal.pone.0065614","article-title":"Latent transforming growth factor \u03b2-binding protein 4 is downregulated in esophageal cancer via promoter methylation","volume":"8","author":"Bultmann","year":"2013","journal-title":"PLoS ONE"},{"key":"2021042501193401200_b5-0080403","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1097\/RLI.0b013e3181b2c135","article-title":"Feasibility of functional cardiac MR imaging in mice using a clinical 3 Tesla whole body scanner","volume":"44","author":"Bunck","year":"2009","journal-title":"Invest. Radiol."},{"key":"2021042501193401200_b6-0080403","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/humu.22165","article-title":"Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa","volume":"34","author":"Callewaert","year":"2013","journal-title":"Hum. Mutat."},{"key":"2021042501193401200_b7-0080403","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1161\/ATVBAHA.109.196725","article-title":"Fibulin-2 and fibulin-5 cooperatively function to form the internal elastic lamina and protect from vascular injury","volume":"30","author":"Chapman","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021042501193401200_b8-0080403","doi-asserted-by":"crossref","first-page":"24553","DOI":"10.1074\/jbc.M109.019364","article-title":"Differential regulation of elastic fiber formation by fibulin-4 and -5","volume":"284","author":"Choudhury","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2021042501193401200_b9-0080403","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/jcp.21643","article-title":"Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity","volume":"219","author":"Dabovic","year":"2009","journal-title":"J. Cell. Physiol."},{"key":"2021042501193401200_b10-0080403","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/jcp.24704","article-title":"Function of latent TGF\u03b2 binding protein 4 and fibulin 5 in elastogenesis and lung development","volume":"230","author":"Dabovic","year":"2015","journal-title":"J. Cell. Physiol."},{"key":"2021042501193401200_b11-0080403","doi-asserted-by":"crossref","first-page":"4195","DOI":"10.1242\/jcs.023820","article-title":"The extracellular matrix at a glance","volume":"123","author":"Frantz","year":"2010","journal-title":"J. Cell Sci."},{"key":"2021042501193401200_b12-0080403","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1111\/j.1540-8175.2006.00323.x","article-title":"Echocardiographic assessment of left ventricular mass in neonatal and adult mice: accuracy of different echocardiographic methods","volume":"23","author":"Ghanem","year":"2006","journal-title":"Echocardiography"},{"key":"2021042501193401200_b13-0080403","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1161\/01.RES.0000260181.19449.95","article-title":"Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice","volume":"100","author":"Hanada","year":"2007","journal-title":"Circ. Res."},{"key":"2021042501193401200_b14-0080403","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1161\/01.RES.0000134921.50377.61","article-title":"Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury","volume":"95","author":"Hilfiker-Kleiner","year":"2004","journal-title":"Circ. Res."},{"key":"2021042501193401200_b15-0080403","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1083\/jcb.200611026","article-title":"Fibulin-5\/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo","volume":"176","author":"Hirai","year":"2007","journal-title":"J. Cell Biol."},{"key":"2021042501193401200_b16-0080403","doi-asserted-by":"crossref","first-page":"19029","DOI":"10.1073\/pnas.0908268106","article-title":"Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase","volume":"106","author":"Horiguchi","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501193401200_b17-0080403","doi-asserted-by":"crossref","first-page":"14387","DOI":"10.1074\/jbc.M210144200","article-title":"Lysyl oxidase is required for vascular and diaphragmatic development in mice","volume":"278","author":"Hornstra","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021042501193401200_b18-0080403","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1074\/jbc.M209256200","article-title":"Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein","volume":"278","author":"Isogai","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021042501193401200_b19-0080403","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1016\/j.yexcr.2008.05.010","article-title":"Fibronectin and heparin binding domains of latent TGF-beta binding protein (LTBP)-4 mediate matrix targeting and cell adhesion","volume":"314","author":"Kantola","year":"2008","journal-title":"Exp. Cell Res."},{"key":"2021042501193401200_b20-0080403","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1002\/jcp.22082","article-title":"Independent regulation of short and long forms of latent TGF-beta binding protein (LTBP)-4 in cultured fibroblasts and human tissues","volume":"223","author":"Kantola","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"2021042501193401200_b21-0080403","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1242\/jcs.115.14.2817","article-title":"Elastic fibres","volume":"115","author":"Kielty","year":"2002","journal-title":"J. Cell Sci."},{"key":"2021042501193401200_b22-0080403","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/30522","article-title":"Elastin is an essential determinant of arterial morphogenesis","volume":"393","author":"Li","year":"1998","journal-title":"Nature"},{"key":"2021042501193401200_b23-0080403","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(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2021042501193401200_b24-0080403","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.1007\/s00018-013-1541-8","article-title":"N-linked glycosylation of the bone morphogenetic protein receptor type 2 (BMPR2) enhances ligand binding","volume":"71","author":"Lowery","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"2021042501193401200_b25-0080403","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S0002-9440(10)61183-2","article-title":"Lysyl oxidase is essential for normal development and function of the respiratory system and for the integrity of elastic and collagen fibers in various tissues","volume":"167","author":"M\u00e4ki","year":"2005","journal-title":"Am. J. Pathol."},{"key":"2021042501193401200_b26-0080403","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1128\/MCB.26.5.1700-1709.2006","article-title":"Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice","volume":"26","author":"McLaughlin","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"2021042501193401200_b27-0080403","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0065-3233(05)70013-9","article-title":"Elastin","volume":"70","author":"Mithieux","year":"2005","journal-title":"Adv. Protein Chem."},{"key":"2021042501193401200_b28-0080403","first-page":"81","article-title":"Latent forms of TGF-beta: molecular structure and mechanisms of activation","volume":"157","author":"Miyazono","year":"1991","journal-title":"Ciba Found. Symp."},{"key":"2021042501193401200_b29-0080403","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/415171a","article-title":"Fibulin-5\/DANCE is essential for elastogenesis in vivo","volume":"415","author":"Nakamura","year":"2002","journal-title":"Nature"},{"key":"2021042501193401200_b30-0080403","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1073\/pnas.1215779110","article-title":"Latent TGF-beta binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5","volume":"110","author":"Noda","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501193401200_b31-0080403","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.matbio.2014.02.004","article-title":"Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies","volume":"37","author":"Papke","year":"2014","journal-title":"Matrix Biol."},{"key":"2021042501193401200_b32-0080403","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1152\/physiolgenomics.00092.2004","article-title":"Fibrillin microfibrils: multipurpose extracellular networks in organismal physiology","volume":"19","author":"Ramirez","year":"2004","journal-title":"Physiol. Genomics"},{"key":"2021042501193401200_b33-0080403","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1093\/cvr\/cvu010","article-title":"Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress","volume":"101","author":"Ricke-Hoch","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"2021042501193401200_b34-0080403","doi-asserted-by":"crossref","first-page":"18459","DOI":"10.1074\/jbc.273.29.18459","article-title":"Identification and characterization of a new latent transforming growth factor-beta-binding protein, LTBP-4","volume":"273","author":"Saharinen","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2021042501193401200_b35-0080403","doi-asserted-by":"crossref","first-page":"4191","DOI":"10.1111\/febs.12012","article-title":"Does human leukocyte elastase degrade intact skin elastin?","volume":"279","author":"Schmelzer","year":"2012","journal-title":"FEBS J."},{"key":"2021042501193401200_b36-0080403","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1080\/10976640600723664","article-title":"How to perform an accurate assessment of cardiac function in mice using high-resolution magnetic resonance imaging","volume":"8","author":"Schneider","year":"2006","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"2021042501193401200_b37-0080403","article-title":"Establishing primary adult fibroblast cultures from rodents","volume":"2033","author":"Seluanov","year":"2010","journal-title":"J. Vis. Exp."},{"key":"2021042501193401200_b38-0080403","doi-asserted-by":"crossref","first-page":"13874","DOI":"10.1074\/jbc.M707820200","article-title":"Targeting of bone morphogenetic protein growth factor complexes to fibrillin","volume":"283","author":"Sengle","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021042501193401200_b39-0080403","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.matbio.2013.10.007","article-title":"LTBP-2 competes with tropoelastin for binding to fibulin-5 and heparin, and is a negative modulator of elastinogenesis","volume":"34","author":"Sideek","year":"2014","journal-title":"Matrix Biol."},{"key":"2021042501193401200_b40-0080403","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1101\/gad.229102","article-title":"Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer","volume":"16","author":"Sterner-Kock","year":"2002","journal-title":"Genes Dev."},{"key":"2021042501193401200_b41-0080403","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1002\/jcb.23385","article-title":"LTBPs, more than just an escort service","volume":"113","author":"Todorovic","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"2021042501193401200_b42-0080403","doi-asserted-by":"crossref","first-page":"11037","DOI":"10.1073\/pnas.1402041111","article-title":"Enhanced receptor-clathrin interactions induced by N-glycan-mediated membrane micropatterning","volume":"111","author":"Torreno-Pina","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501193401200_b43-0080403","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.ajhg.2009.09.013","article-title":"Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development","volume":"85","author":"Urban","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"2021042501193401200_b44-0080403","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1093\/jb\/mvn014","article-title":"Characterization of the molecular interaction between tropoelastin and DANCE\/fibulin-5","volume":"143","author":"Wachi","year":"2008","journal-title":"J. Biochem."},{"key":"2021042501193401200_b45-0080403","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/bdrc.20111","article-title":"New insights into elastic fiber assembly","volume":"81","author":"Wagenseil","year":"2007","journal-title":"Birth Defects Res. C Embryo Today"},{"key":"2021042501193401200_b46-0080403","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1267\/ahc.10026","article-title":"Fibulin-4 and -5, but not Fibulin-2, are associated with Tropoelastin deposition in elastin-producing cell culture","volume":"43","author":"Yamauchi","year":"2010","journal-title":"Acta Histochem. Cytochem."},{"key":"2021042501193401200_b47-0080403","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/j.biocel.2010.03.009","article-title":"Unraveling the mechanism of elastic fiber assembly: the roles of short fibulins","volume":"42","author":"Yanagisawa","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2021042501193401200_b48-0080403","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/415168a","article-title":"Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo","volume":"415","author":"Yanagisawa","year":"2002","journal-title":"Nature"},{"key":"2021042501193401200_b49-0080403","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1242\/jcs.02800","article-title":"Connexin31 cannot functionally replace connexin43 during cardiac morphogenesis in mice","volume":"119","author":"Zheng-Fischh\u00f6fer","year":"2006","journal-title":"J. Cell Sci."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/8\/4\/403\/1868539\/403_dmm018960.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.018960\/2032122\/dmm_018960.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.018960\/2032122\/dmm_018960.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T12:13:43Z","timestamp":1717762423000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.018960\/261869\/Modeling-autosomal-recessive-cutis-laxa-type-1C"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,1]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1242\/dmm.018960","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2015,1,1]]},"article-number":"dmm.018960"}}