title: Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity.
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.
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Branka
authors.initials: B
authors.lastname: Dabovic
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Jiwon
authors.initials: J
authors.lastname: Choi
authors.forename: Melinda
authors.initials: M
authors.lastname: Vassallo
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
authors.forename: Harald
authors.initials: H
authors.lastname: von Melchner
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
mesh_terms: D000818:Animals; D001549:Benzamides / Q000378:metabolism; D004149:Dioxoles / Q000378:metabolism; D004549:Elastin / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000033:anatomy & histology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000502:physiology / Q000648:ultrastructure; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; C538753:LTBP-4 protein, mouse; D053779:Latent TGF-beta Binding Proteins; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004549:Elastin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I