title: Rac1 modulates mammalian lung branching morphogenesis in part through canonical Wnt signaling.
abstract: Lung branching morphogenesis relies on a number of factors, including proper epithelial cell proliferation and differentiation, cell polarity, and migration. Rac1, a small Rho GTPase, orchestrates a number of these cellular processes, including cell proliferation and differentiation, cellular alignment, and polarization. Furthermore, Rac1 modulates both noncanonical and canonical Wnt signaling, important pathways in lung branching morphogenesis. Culture of embryonic mouse lung explants in the presence of the Rac1 inhibitor (NSC23766) resulted in a dose-dependent decrease in branching. Increased cell death and BrdU uptake were notably seen in the mesenchyme, while no direct effect on the epithelium was observed. Moreover, vasculogenesis was impaired following Rac1 inhibition as shown by decreased Vegfa expression and impaired LacZ staining in Flk1-Lacz reporter mice. Rac1 inhibition decreased Fgf10 expression in conjunction with many of its associated factors. Moreover, using the reporter lines TOPGAL and Axin2-LacZ, there was an evident decrease in canonical Wnt signaling in the explants treated with the Rac1 inhibitor. Activation of canonical Wnt pathway using WNT3a or WNT7b only partially rescued the branching inhibition. Moreover, these results were validated on human explants, where Rac1 inhibition resulted in impaired branching and decreased AXIN2 and FGFR2b expression. We therefore conclude that Rac1 regulates lung branching morphogenesis, in part through canonical Wnt signaling. However, the exact mechanisms by which Rac1 interacts with canonical Wnt in human and mouse lung requires further investigation.
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Soula
authors.initials: S
authors.lastname: Danopoulos
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Krainock
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Omar
authors.initials: O
authors.lastname: Toubat
authors.affiliation: Maternal Fetal Medicine Division, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Matthew
authors.initials: M
authors.lastname: Thornton
authors.affiliation: Maternal Fetal Medicine Division, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Brendan
authors.initials: B
authors.lastname: Grubbs
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; dalalam@chla.usc.edu.|Keck School of Medicine, University of Southern California, Los Angeles, California; and.
authors.forename: Denise
authors.initials: D
authors.lastname: Al Alam
mesh_terms: D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D051526:Fibroblast Growth Factor 10; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000196:embryology* / Q000378:metabolism*; D008322:Mammals / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D018919:Neovascularization, Physiologic; D060449:Wnt Signaling Pathway; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C496463:FGF10 protein, human; D051526:Fibroblast Growth Factor 10; D020830:rac1 GTP-Binding Protein
keywords: Rac1; branching morphogenesis; canonical WNT; lung