2. Academic Validation
  3. Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils

Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils

  • Hum Mol Genet. 2014 Nov 1;23(21):5672-82. doi: 10.1093/hmg/ddu283.
Tadashi Inoue 1,  Tetsuya Ohbayashi 2,  Yusuke Fujikawa 3,  Hideyuki Yoshida 4,  Tomoya O Akama 5,  Kazuo Noda 6,  Masahito Horiguchi 7,  Katsuro Kameyama 8,  Yoshio Hata 8,  Kanji Takahashi 9,  Kenji Kusumoto 10,  Tomoyuki Nakamura 11
Affiliations

Affiliations

  • 1 Department of Pharmacology, Department of Plastic and Reconstructive Surgery.
  • 2 Division of Laboratory Animal Science, Research Center for Bioscience and Technology and.
  • 3 Department of Pharmacology, Department of Cardiology and.
  • 4 Department of Pharmacology, Department of Ophthalmology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
  • 5 Department of Pharmacology, Tumor Microenvironment Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
  • 6 Department of Pharmacology, Department of Plastic and Reconstructive Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan and.
  • 7 Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
  • 8 Division of Integrative Bioscience, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Sciences, Yonago, Tottori 683-8503, Japan.
  • 9 Department of Ophthalmology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
  • 10 Department of Plastic and Reconstructive Surgery.
  • 11 Department of Pharmacology, nakamtom@hirakata.kmu.ac.jp.
PMID: 24908666 DOI: 10.1093/hmg/ddu283
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.

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