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© The Rockefeller University Press, 0021-9525/1997//193 $5.00
The Journal of Cell Biology, Volume 136, Number 1, , 1997 193-204

Extracellular Fibrillar Structure of Latent TGFβ Binding Protein-1: Role in TGFβ-dependent Endothelial-Mesenchymal Transformation during Endocardial Cushion Tissue Formation in Mouse Embryonic Heart

Department of Anatomy, Saitama Medical School, Moroyama-cho, Iruma-gun, Saitama, 350-04 Japan; and ^* Department of Biochemistry, The Cancer Institute, Japanese Foundation for Cancer Research, Kami-Ikebukuro, Toshima-ku, Tokyo, 170 Japan

Transforming growth factor-β (TGFβ) is a dimeric peptide growth factor which regulates cellular differentiation and proliferation during development. Most cells secrete TGFβ as a large latent TGFβ complex containing mature TGFβ, latency associated peptide, and latent TGFβ-binding protein (LTBP)-1. The biological role of LTBP-1 in development remains unclear. Using a polyclonal antiserum specific for LTBP-1 (Ab39) and three-dimensional collagen gel culture assay of embryonic heart, we examined the tissue distribution of LTBP-1 and its functional role during the formation of endocardial cushion tissue in the mouse embryonic heart. Mature TGFβ protein was required at the onset of the endothelial-mesenchymal transformation to initiate endocardial cushion tissue formation. Double antibody staining showed that LTBP-1 colocalized with TGFβ1 as an extracellular fibrillar structure surrounding the endocardial cushion mesenchymal cells. Immunogold electronmicroscopy showed that LTBP-1 localized to 40–100 nm extracellular fibrillar structure and 5–10-nm microfibrils. The anti–LTBP-1 antiserum (Ab39) inhibited the endothelial-mesenchymal transformation in atrio-ventricular endocardial cells cocultured with associated myocardium on a three-dimensional collagen gel lattice. This inhibitory effect was reversed by administration of mature TGFβ proteins in culture. These results suggest that LTBP-1 exists as an extracellular fibrillar structure and plays a role in the storage of TGFβ as a large latent TGFβ complex.

Abbreviations used in this paper: AV, atrioventricular; EX, explant; LAP, latency associated peptide; LTBP, latent transforming growth factor-β; binding protein; M, myocardium; Me, mesenchymal cell; OT, outflow tract; PL, plasmin.

Please address all correspondence to Y. Nakajima, Department of Anatomy, Saitama Medical School, 38 Morophongo, Moroyama-cho, Irumagun, Saitama 350-04 Japan. Tel: 81 492 76 1148. Fax: 81 492 95 8026.

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