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. J. Cell. Physiol. 219: 14–22, 2009. © 2008 Wiley‐Liss, Inc.