Epithelium-specific adenoviral transfer of a dominant-negative mutant TGF-β type II receptor stimulates embryonic lung branching morphogenesis in culture and potentiates EGF and PDGF-AA

نویسندگان

  • Jingsong Zhao
  • Patricia J. Sime
  • Pablo Bringas
  • Jack Gauldie
  • David Warburton
چکیده

Although exogenous transforming growth factor-beta (TGF-beta) is known to inhibit branching morphogenesis in mouse embryonic lungs in culture, whether the principal negative function of endogenous TGF-beta signaling resides in lung epithelium or mesenchyme remains unresolved. A recombinant adenovirus was constructed, containing a mutated human TGF-beta type II receptor with a truncated cytoplasmic kinase domain. We examined whether this dominant-negative receptor could abolish epithelium-specific endogenous TGF-beta signaling. We introduced the recombinant adenovirus into lung explants via intra-tracheal micro-injection. This resulted in over-expression of exogenous truncated TGF-beta type II receptor only in airway epithelium, not in mesenchyme, as assessed by mRNA level and protein localization. Blockade of endogenous TGF-beta receptor signaling in epithelial endoderm by the mutated dominant-negative TGF-beta type II receptor resulted in significant (65%) stimulation of epithelial branching morphogenesis, while exogenous TGF-beta no longer downregulated epithelial PCNA immunoreactivity and surfactant protein C (SP-C) expression. Additionally, the mitogenic responses to epidermal growth factor (EGF) and platelet-derived growth factor, PDGF-AA were potentiated by 33 and 31%, respectively. We conclude that epithelium-specific adenovirus-mediated over-expression of a dominant-negative TGF-beta type II receptor completely and specifically abolished the anti-proliferative effects of both endogenous and exogenous TGF-beta. Therefore, epithelium-specific TGF-beta signaling is sufficient to negatively regulate embryonic lung-branching morphogenesis in culture. We speculate that abrogation of TGF-beta signaling stimulates lung morphogenesis by potentiating the inductive and permissive effects of other endogenous peptide growth factors such as EGF and PDGF-AA.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

The biological role of platelet-derived growth factor (PDGF)-AA in lung morphogenesis was investigated by incubating embryonic lung explants with phosphorothioate antisense PDGF-A oligonucleotides, which decreased PDGF-AA but not PDGF-BB protein content. Antisense PDGF-A oligonucleotides inhibited DNA

Branching morphogenesis of many organs, including lung, has been shown to take place in response to epithelial-mesenchymal tissue interactions (Rudnick, 1933; Wessels, 1977). The molecular signals guiding branching morphogenesis are largely unknown. As branching morphogenesis involves cell proliferation, migration and differentiation, the ontogenic sequence of these events in early lung organog...

متن کامل

Adenovirus-mediated decorin gene transfer prevents TGF-β-induced inhibition of lung morphogenesis.

Excessive transforming growth factor (TGF)-β signaling has been implicated in pulmonary hypoplasia associated with bronchopulmonary dysplasia, a chronic lung disease of human prematurity featuring pulmonary fibrosis. This implies that inhibitors of TGF-β could be useful therapeutic agents. Because exogenous TGF-β ligands are known to inhibit lung branching morphogenesis and cytodifferentiation ...

متن کامل

Abrogation of betaglycan attenuates TGF-β-mediated inhibition of embryonic murine lung branching morphogenesis in culture

Although betaglycan (TGF-beta type III receptor) is known to enhance TGF-beta ligand binding to its type II receptor in murine lung epithelial cell lines, the biological significance of this phenomenon in the process of lung organogenesis is not understood. Betaglycan gene expression was detected in embryonic murine lungs undergoing branching morphogenesis in ex vivo culture. Antisense betaglyc...

متن کامل

Smad7 is a TGF-β-inducible attenuator of Smad2/3-mediated inhibition of embryonic lung morphogenesis

Smad7 was recently shown to antagonize TGF-beta-induced activation of signal-transducing Smad2 and Smad3 proteins. However, the biological function of Smad7 in the process of lung organogenesis is not known. Since Smad2/3-mediated TGF-beta signaling is known to inhibit embryonic lung branching morphogenesis, we tested the hypothesis that Smad7 regulates early lung development by modulating TGF-...

متن کامل

Overexpression of a Kinase-deficient Transforming Growth Factor-b Type II Receptor in Mouse Mammary Stroma Results in Increased Epithelial Branching

Members of the transforming growth factor-b (TGF-b) superfamily signal through heteromeric type I and type II serine/threonine kinase receptors. Transgenic mice that overexpress a dominant-negative mutation of the TGF-b type II receptor (DNIIR) under the control of a metallothionein-derived promoter (MT-DNIIR) were used to determine the role of endogenous TGF-bs in the developing mammary gland....

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Mechanisms of Development

دوره 72  شماره 

صفحات  -

تاریخ انتشار 1998