title: Function of latent TGFβ binding protein 4 and fibulin 5 in elastogenesis and lung development.
abstract: Mice deficient in Latent TGFβ Binding Protein 4 (Ltbp4) display a defect in lung septation and elastogenesis. The lung septation defect is normalized by genetically decreasing TGFβ2 levels. However, the elastic fiber assembly is not improved in Tgfb2(-/-) ;Ltbp4S(-/-) compared to Ltbp4S(-/-) lungs. We found that decreased levels of TGFβ1 or TGFβ3 did not improve lung septation indicating that the TGFβ isoform elevated in Ltbp4S(-/-) lungs is TGFβ2. Expression of a form of Ltbp4 that could not bind latent TGFβ did not affect lung phenotype indicating that normal lung development does not require the formation of LTBP4-latent TGFβ complexes. Therefore, the change in TGFβ-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 TGFβ2 in lung septation and for Ltbp4 in regulating fibulin-5 dependent elastic fiber assembly.
authors: Departments of Cell Biology, New York University Medical Center, 550 First Avenue, New York, NY, USA.
authors: Branka
authors: B
authors: Dabovic
authors: Ian B
authors: IB
authors: Robertson
authors: Lior
authors: L
authors: Zilberberg
authors: Melinda
authors: M
authors: Vassallo
authors: Elaine C
authors: EC
authors: Davis
authors: Daniel B
authors: DB
authors: Rifkin
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D004547:Elastic Tissue / Q000002:abnormalities / Q000196:embryology*; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071837:Fibrillins; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000002:abnormalities / Q000196:embryology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; C120769:Fbln5 protein, mouse; D000071837:Fibrillins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; C509042:Tgfb2 protein, mouse; D053781:Transforming Growth Factor beta2; D004549:Elastin