title: Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils.
abstract: Latent TGF-β-binding protein-2 (LTBP-2) is an extracellular matrix protein associated with microfibrils. Homozygous mutations in LTBP2 have been found in humans with genetic eye diseases such as congenital glaucoma and microspherophakia, indicating a critical role of the protein in eye development, although the function of LTBP-2 in vivo has not been well understood. In this study, we explore the in vivo function of LTBP-2 by generating Ltbp2(-/-) mice. Ltbp2(-/-) mice survived to adulthood but developed lens luxation caused by compromised ciliary zonule formation without a typical phenotype related to glaucoma, suggesting that LTBP-2 deficiency primarily causes lens dislocation but not glaucoma. The suppression of LTBP2 expression in cultured human ciliary epithelial cells by siRNA disrupted the formation of the microfibril meshwork by the cells. Supplementation of recombinant LTBP-2 in culture medium not only rescued the microfibril meshwork formation in LTBP2-suppressed ciliary epithelial cells but also restored unfragmented and bundled ciliary zonules in Ltbp2(-/-) mouse eyes under organ culture. Although several reported human mutant LTBP-2 proteins retain normal domain structure and keep the fibrillin-1-binding site intact, none of these mutant proteins were secreted from their producing cells, suggesting secretion arrest occurred to the LTBP-2 mutants owing to conformational alteration. The findings of this study suggest that LTBP-2 is an essential component for the formation of microfibril bundles in ciliary zonules.
authors.affiliation: Department of Pharmacology, Department of Plastic and Reconstructive Surgery.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Laboratory Animal Science, Research Center for Bioscience and Technology and.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohbayashi
authors.affiliation: Department of Pharmacology, Department of Cardiology and.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujikawa
authors.affiliation: Department of Pharmacology, Department of Ophthalmology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Pharmacology, Tumor Microenvironment Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Tomoya O
authors.initials: TO
authors.lastname: Akama
authors.affiliation: Department of Pharmacology, Department of Plastic and Reconstructive Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan and.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Noda
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Masahito
authors.initials: M
authors.lastname: Horiguchi
authors.affiliation: Division of Integrative Bioscience, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Sciences, Yonago, Tottori 683-8503, Japan.
authors.forename: Katsuro
authors.initials: K
authors.lastname: Kameyama
authors.affiliation: Division of Integrative Bioscience, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Sciences, Yonago, Tottori 683-8503, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hata
authors.affiliation: Department of Ophthalmology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Plastic and Reconstructive Surgery.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kusumoto
authors.affiliation: Department of Pharmacology, nakamtom@hirakata.kmu.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D002460:Cell Line; D002923:Cilia / Q000235:genetics*; D004479:Ectopia Lentis / Q000235:genetics / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D000071838:Fibrillin-1; D000071837:Fibrillins; D055786:Gene Knockout Techniques; D018390:Gene Targeting; D005838:Genotype; D005901:Glaucoma / Q000235:genetics; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020894:Microfibrils / Q000235:genetics*; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C509035:LTBP2 protein, human