title: Smad1 and its target gene Wif1 coordinate BMP and Wnt signaling activities to regulate fetal lung development.
abstract: Bone morphogenetic protein 4 (Bmp4) is essential for lung development. To define the intracellular signaling mechanisms by which Bmp4 regulates lung development, BMP-specific Smad1 or Smad5 was selectively knocked out in fetal mouse lung epithelial cells. Abrogation of lung epithelial-specific Smad1, but not Smad5, resulted in retardation of lung branching morphogenesis and reduced sacculation, accompanied by altered distal lung epithelial cell proliferation and differentiation and, consequently, severe neonatal respiratory failure. By combining cDNA microarray with ChIP-chip analyses, Wnt inhibitory factor 1 (Wif1) was identified as a novel target gene of Smad1 in the developing mouse lung epithelial cells. Loss of Smad1 transcriptional activation of Wif1 was associated with reduced Wif1 expression and increased Wnt/β-catenin signaling activity in lung epithelia, resulting in specific fetal lung abnormalities. This suggests a novel regulatory loop of Bmp4-Smad1-Wif1-Wnt/β-catenin in coordinating BMP and Wnt pathways to control fetal lung development.
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Song-Guo
authors.initials: SG
authors.lastname: Zheng
authors.forename: Pablo
authors.initials: P
authors.lastname: Bringas
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhou
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Lieve
authors.initials: L
authors.lastname: Umans
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004847:Epithelial Cells; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051898:Smad1 Protein; C118544:Wif1 protein, mouse; D051153:Wnt Proteins