Control of lung development by latent TGF‐β binding proteins

The latent TGF‐β binding proteins (LTBP‐1 ‐3, and ‐4) assist in the secretion and localization of latent TGF‐β molecules. Ltbp3−/−and Ltbp4S−/− mice have distinct phenotypes and only in the lungs does deficiency of either Ltbp‐3 or Ltbp‐4 cause developmental abnormalities. To determine if these two LTBPs have additional common functions, we generated mice deficient for both Ltbp‐3 and Ltbp‐4S. The only novel defect in Ltbp3−/−;Ltbp4S−/− mice was an early lethality compared to mice with single mutations. In addition lung abnormalities were exacerbated and the terminal air sac septation defect was more severe in Ltbp3−/−;Ltbp4S−/− mice than in Ltbp4S−/− mice. Decreased cellularity of Ltbp3−/−;Ltbp4S−/− lungs was correlated with higher rate of apoptosis in newborn lungs of Ltbp3−/−;Ltbp4S−/− animals compared to WT, Ltbp3−/−, and Ltbp4S−/− mice. No differences in the maturation of the major lung cell types were discerned between the single and double mutant mice. However, the distribution of type 2 cells and myofibroblasts was abnormal, and myofibroblast segregation in some areas might be an indication of early fibrosis. We also observed differences in ECM composition between Ltbp3−/−;Ltbp4S−/− and Ltbp4S−/− lungs after birth, reflected in decreased incorporation of fibrillin‐1 and ‐2 in Ltbp3−/−;Ltbp4S−/− matrix. The function of the lungs of Ltbp3−/−;Ltbp4S−/− mice after the first week of life was potentially further compromised by macrophage infiltration, as proteases secreted from macrophages might exacerbate developmental emphysema. Together these data indicate that LTBP‐3 and ‐4 perform partially overlapping functions only in the lungs. J. Cell. Physiol. 226: 1499–1509, 2011. © 2010 Wiley‐Liss, Inc.