title: Tbx2 and Tbx3 Act Downstream of Shh to Maintain Canonical Wnt Signaling during Branching Morphogenesis of the Murine Lung.
abstract: Numerous signals drive the proliferative expansion of the distal endoderm and the underlying mesenchyme during lung branching morphogenesis, but little is known about how these signals are integrated. Here, we show by analysis of conditional double mutants that the two T-box transcription factor genes Tbx2 and Tbx3 act together in the lung mesenchyme to maintain branching morphogenesis. Expression of both genes depends on epithelially derived Shh signaling, with additional modulation by Bmp, Wnt, and Tgfβ signaling. Genetic rescue experiments reveal that Tbx2 and Tbx3 function downstream of Shh to maintain pro-proliferative mesenchymal Wnt signaling, in part by direct repression of the Wnt antagonists Frzb and Shisa3. In combination with our previous finding that Tbx2 and Tbx3 repress the cell-cycle inhibitors Cdkn1a and Cdkn1b, we conclude that Tbx2 and Tbx3 maintain proliferation of the lung mesenchyme by way of at least two molecular mechanisms: regulating cell-cycle regulation and integrating the activity of multiple signaling pathways.
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Timo H
authors.initials: TH
authors.lastname: Lüdtke
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Rudat
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Wojahn
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Anna-Carina
authors.initials: AC
authors.lastname: Weiss
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Marc-Jens
authors.initials: MJ
authors.lastname: Kleppa
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kurz
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Henner F
authors.initials: HF
authors.lastname: Farin
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Moon
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany. Electronic address: kispert.andreas@mh-hannover.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D012097:Repressor Proteins / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000099274:Frizzled-Related Proteins
chemical_list: D019485:Bone Morphogenetic Proteins; D006023:Glycoproteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D016212:Transforming Growth Factor beta; D000099274:Frizzled-Related Proteins; C465570:Shh protein, mouse; C097348:T-Box Domain Protein 2; C491460:Tbx3 protein, mouse