J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/01/193/12 $2.00
Volume 136, Number 1, January 13, 1997 193-204

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

Yuji Nakajima, Kohei Miyazono,^* Mitsuyasu Kato,^* Masao Takase, Toshiyuki Yamagishi, and Hiroaki Nakamura

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- (TGF) is a dimeric peptide growth factor which regulates cellular differentiation and proliferation during development. Most cells secrete TGF as a large latent TGF complex containing mature TGF, latency associated peptide, and latent TGF-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 TGF 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 TGF1 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 TGF proteins in culture. These results suggest that LTBP-1 exists as an extracellular fibrillar structure and plays a role in the storage of TGF as a large latent TGF complex.

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