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Function of latent TGF? binding protein 4 and fibulin 5 in elastogenesis and lung development.

ABSTRACT: Mice deficient in Latent TGF? Binding Protein 4 (Ltbp4) display a defect in lung septation and elastogenesis. The lung septation defect is normalized by genetically decreasing TGF?2 levels. However, the elastic fiber assembly is not improved in Tgfb2(-/-) ;Ltbp4S(-/-) compared to Ltbp4S(-/-) lungs. We found that decreased levels of TGF?1 or TGF?3 did not improve lung septation indicating that the TGF? isoform elevated in Ltbp4S(-/-) lungs is TGF?2. Expression of a form of Ltbp4 that could not bind latent TGF? did not affect lung phenotype indicating that normal lung development does not require the formation of LTBP4-latent TGF? complexes. Therefore, the change in TGF?-level in the lungs is not directly related to Ltbp4 deficiency but probably is a consequence of changes in the extracellular matrix. Interestingly, combination of the Ltbp4S(-/-) mutation with a fibulin-5 null mutant in Fbln5(-/-) ;Ltbp4S(-/-) mice improves the lung septation compared to Ltbp4S(-/-) lungs. Large globular elastin aggregates characteristic for Ltbp4S(-/-) lungs do not form in Fbln5(-/-) ;Ltbp4S(-/-) lungs and EM studies showed that elastic fibers in Fbln5(-/-) ;Ltbp4S(-/-) lungs resemble those found in Fbln5(-/-) mice. These results are consistent with a role for TGF?2 in lung septation and for Ltbp4 in regulating fibulin-5 dependent elastic fiber assembly.

PROVIDER: S-EPMC4436707 | BioStudies |

REPOSITORIES: biostudies

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