Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-β activity

The latent TGF-β binding proteins (LTBP) -1,-3, and -4 are extracellular proteins that assist in the secretion and localization of latent TGF-β. The null mutation of LTBP-4S in mice causes defects in the differentiation of terminal air-sacs, fragmented elastin, and colon carcinomas. We investigated lung development from embryonic day 14.5 (E14.5) to day 7 after birth (P7) in order to determine when the defects in elastin organization initiate and to further examine the relation of TGF-β signaling levels and air-sac septation in Ltbp4S-/- lungs. We found that defects in elastogenesis are visible as early as E14.5 and are maintained in the alveolar walls, in blood vessel media, and subjacent airway epithelium. The air-sac septation defect was associated with excessive TGF-β signaling and was reversed by lowering TGF-β2 levels. Thus, the phenotype is not directly reflective of a change in TGF-β1, the only TGF-β isoform known to complex with LTBP-4. Reversal of the air-sac septation defect was not associated with normalization of the elastogenesis indicating two separate functions of LTBP-4 as a regulator of elastic fiber assembly and TGF-β levels in lungs.