Control of lung development by latent TGF-β binding proteins

Branka Dabovic, Yan Chen, Jiwon Choi, Elaine C. Davis, Lynn Y. Sakai, Vesna Todorovic, Melinda Vassallo, Lior Zilberberg, Amanjot Singh, Daniel B. Rifkin

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1499-1509
Number of pages11
JournalJournal of Cellular Physiology
Issue number6
StatePublished - Jun 2011
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology


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