title: Latent TGF-β binding protein 2 and 4 have essential overlapping functions in microfibril development.
abstract: Microfibrils are exracellular matrix components necessary for elastic fiber assembly and for suspending lenses. We previously reported that latent TGF-β binding protein 2 (LTBP-2), a microfibril-associated protein, is required for forming stable microfibril bundles in ciliary zonules. However, it was not understood why Ltbp2 null mice only showed an eye-specific phenotype, whereas LTBP-2 is abundantly expressed in other tissues containing microfibrils in wild type mice. Here, we show that LTBP-4, another microfibril-associated protein, compensates for the loss of LTBP-2 in microfibril formation. Ltbp2/4S double knockout (DKO) mice showed increased lethality due to emphysema, which was much more severe than that found in Ltbp4S null mice. Elastic fibers in the lungs of Ltbp2/4S DKO mice were severely disorganized and fragmented. Cultured mouse embryonic fibroblasts (MEFs) from Ltbp2/4S DKO embryos developed reduced microfibril meshwork in serum-free conditions, whereas the microfibril formation was restored by the addition of either recombinant LTBP-2 or -4. Finally, ectopic expression of LTBP-4 in the whole body restored ciliary zonule microfibril bundles in the eyes of Ltbp2 null mice. These data suggest that LTBP-2 and -4 have critical overlapping functions in forming the robust structure of microfibrils in vitro and in vivo.
authors.affiliation: Department of Pharmacology, Kansai Medical University, Osaka, 573-1010, Japan.|Department of Cardiology, Kansai Medical University, Osaka, 573-1010, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujikawa
authors.affiliation: Department of Pharmacology, Kansai Medical University, Osaka, 573-1010, Japan.|Department of Ophthalmology, Kansai Medical University, Osaka, 753-1010, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Pharmacology, Kansai Medical University, Osaka, 573-1010, Japan.|Department of Plastic and Reconstructive Surgery, Kansai Medical University, Osaka, 573-1010, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University Graduate School of Medical Sciences, Yonago, Tottori, 683-8503, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohbayashi
authors.affiliation: Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Noda
authors.affiliation: Department of Molecular Hematology, University of Frankfurt Medical School, Frankfurt am Main, 60590, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: von Melchner
authors.affiliation: Department of Cardiology, Kansai Medical University, Osaka, 573-1010, Japan.
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
authors.affiliation: Department of Cardiology, Kansai Medical University, Osaka, 573-1010, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.affiliation: Department of Pharmacology, Kansai Medical University, Osaka, 573-1010, Japan.
authors.forename: Tomoya O
authors.initials: TO
authors.lastname: Akama
authors.affiliation: Department of Pharmacology, Kansai Medical University, Osaka, 573-1010, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism; D004646:Emphysema / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D005838:Genotype; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D020894:Microfibrils / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C538753:LTBP-4 protein, mouse; D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; C509036:Ltbp2 protein, mouse; D012333:RNA, Messenger