ARRESTED LUNG MORPHOGENESIS IN TRANSGENIC MICE BEARING AN SP-C-TGF-BETA-1 CHIMERIC GENE

Transforming growth factor-beta 1 (TGF-beta 1) influences the morphoge nesis of many organs, regulating cell growth, differentiation, gene ex pression, extracellular matrix deposition, and angiogenesis. In order to assess the effects of TGF-beta 1 on lung development in vivo, trans genic mice were generated bearing a chimeric gene composed of human su rfactant protein C (SP-C) gene promoter and the porcine TGF-beta 1 cDN A mutated to ensure constitutive activation of the TGF-beta 1 peptide. Because of the perinatal loss related to the SP-C-TGF-beta 1 transgen e, embryos bearing the transgene were obtained on Days 16 and 18.5 of gestation. TGF-beta 1 was selectively expressed in respiratory epithel ial cells of the transgenic embryos. Body weight, length, and lung siz e were not altered in the transgenic embryos; however, lung morphogene sis of Day 18.5 transgenic mice was arrested in a late pseudoglandular stage of development, while that of their nontransgenic littermates w as typical of the saccular stage. Lungs of transgenic mice on Day 16 c ontained fewer acinar buds than those of nontransgenic Littermates. At both ages, epithelial cell differentiation, assessed by the expressio n of Clara cell secretory protein(2) and pro-SP-C, was inhibited. Whil e collagen III deposition was not affected by the transgene, collagen I expression was persistent in terminal airways of fd 18.5 transgenic lungs. The distribution of alpha-smooth muscle actin was markedly alte red, being detected in the mesenchyme surrounding the distal leading e dges of epithelial tubules in the SP-C-TGF-beta 1 transgenic mice. Exp ression of TGF-beta 1 in the developing respiratory epithelium of tran sgenic mice arrested lung sacculation and epithelial cell differentiat ion in vivo, supporting the role of TGF-beta family members in lung mo rphogenesis and differentiation. (C) 1996 Academic Press, Inc.