TY - JOUR
T1 - Dual functions for LTBP in lung development
T2 - LTBP-4 independently modulates elastogenesis and TGF-β activity
AU - Dabovic, Branka
AU - Chen, Yan
AU - Choi, Jiwon
AU - Vassallo, Melinda
AU - Dietz, Harry C.
AU - Ramirez, Francesco
AU - Von Melchner, Harald
AU - Davis, Elaine C.
AU - Rifkin, Daniel B.
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=60849117528&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=60849117528&partnerID=8YFLogxK
U2 - 10.1002/jcp.21643
DO - 10.1002/jcp.21643
M3 - Article
C2 - 19016471
AN - SCOPUS:60849117528
VL - 219
SP - 14
EP - 22
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
SN - 0021-9541
IS - 1
ER -