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Generation of mice with a conditional allele for the transforming growth factor beta3 gene.

ABSTRACT: The transforming growth factor beta (TGF?) pathway is involved in embryonic development and several inherited and acquired human diseases. The gene for TGF?3 (Tgfb3) encodes one of the three ligands for TGF? receptors. It is widely expressed in the embryo and its mutation or misexpression is found in human diseases. Tgfb3-/- mice die at birth from cleft palate, precluding functional studies in adults. Here, we generated mice in which exon 6 of Tgfb3 was flanked with LoxP sites (Tgfb3flox/flox). The adult mice were normal and fertile. EIIa-Cre-mediated deletion of exon 6 in Tgfb3flox/flox mice efficiently generated Tgfb3 conditional knockout (Tgfb3cko/cko) mice which died at birth from the same cleft palate defect as Tgfb3-/- mice, indicating that the conditional and knockout alleles are functionally equivalent. This Tgfb3cko allele will now enable studies of TGF?3 function in different cell or tissue types in embryonic development and during adulthood.

SUBMITTER: Doetschman T

PROVIDER: S-EPMC3850393 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Generation of mice with a conditional allele for the transforming growth factor beta3 gene.

Doetschman Thomas T Georgieva Teodora T Li Hongqi H Reed Thomas D TD Grisham Christina C Friel Jacqueline J Estabrook Mark A MA Gard Connie C Sanford L P LP Azhar Mohamad M

Genesis (New York, N.Y. : 2000) 20120106 1

The transforming growth factor beta (TGFβ) pathway is involved in embryonic development and several inherited and acquired human diseases. The gene for TGFβ3 (Tgfb3) encodes one of the three ligands for TGFβ receptors. It is widely expressed in the embryo and its mutation or misexpression is found in human diseases. Tgfb3-/- mice die at birth from cleft palate, precluding functional studies in adults. Here, we generated mice in which exon 6 of Tgfb3 was flanked with LoxP sites (Tgfb3flox/flox). ...[more]

PMID: 22223248

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Project description:Embryonic heart valve primordia (cushions) maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV) cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ) and serotonin (5-HT) signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA) and extracellular matrix expression (col1α2) in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT), resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical remodeling of AV cushions during development.

Dataset Information

Generation of mice with a conditional allele for the transforming growth factor beta3 gene.

Publications

Generation of mice with a conditional allele for the transforming growth factor beta3 gene.

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