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J Cell Physiol. 2009 Apr;219(1):14-22. doi: 10.1002/jcp.21643.

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

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1
Department of Cell Biology, New York University School of Medicine, New York, New York, USA.

Abstract

The latent TGF-beta binding proteins (LTBP) -1, -3, and -4 are extracellular proteins that assist in the secretion and localization of latent TGF-beta. 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-beta 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-beta signaling and was reversed by lowering TGF-beta2 levels. Thus, the phenotype is not directly reflective of a change in TGF-beta1, the only TGF-beta 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-beta levels in lungs.

PMID:
19016471
PMCID:
PMC2719250
DOI:
10.1002/jcp.21643
[Indexed for MEDLINE]
Free PMC Article

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