Tgfβ signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development

Jiao, Kai; Langworthy, Melissa; Batts, Lorene; Brown, Chris; Moses, Harold L.; Baldwin, H. Scott

doi:10.1242/dev.02597

Cited by 93 publications

(104 citation statements)

References 38 publications

(55 reference statements)

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“…One further embryo had a perimembranous VSD with an overriding aorta. The low incidence of defects in the Mlc2v-Cre/ Tgfbr2 fl/D embryos is similar to that reported for the myocardial-restricted Tgfbr2 KO embryos generated using cTnT-Cre/Tgfbr2fl/fl mice where only 8% of embryos were affected, one with a VSD and one with a VSD plus double outlet right ventricle (Jiao et al, 2006). Two independent models targeting Tgfbr2 expression in the myocardium, therefore, produced normal cardiac development in the majority of cases.…”

Section: (Asterisk) Efsupporting

confidence: 79%

“…Consistent with this role, it has been shown that loss of the TGFb2 ligand is associated with deficient ventricular septation (Sanford et al, 1997;Bartram et al, 2001), and that TGFb1 mutant mice exhibit disorganised valves, albeit only in certain genetic backgrounds (Letterio et al, 1994). More recent advances in mouse genetics have permitted in vivo analysis of TGFb signalling during cardiac development in a cell type-specific manner, and have confirmed the importance of the main type I and type II TGFb receptors (Jiao et al, 2006;Sridurongrit et al, 2008). Overall, evidence produced to date suggests a critical role for these TGFb receptors in endothelial cells (ECs), a role that is required to promote formation of the cardiac cushions (Sridurongrit et al, 2008).…”

Section: Introductionmentioning

confidence: 90%

“…However, the role of TGFb signalling in these processes has not yet been determined. Furthermore, in light of evidence that Tgfbr2 is important in endothelial cells during cardiac development (Jiao et al, 2006), and to bypass the embryonic lethality at E10.5 to E11.5 seen in the Jiao et al (2006) study, we used the tamoxifen-inducible Cdh5(PAC)-CreERT2 line (Mahmoud et al, 2010). This permitted us to control the timing of endothelial Cre activity, and to inactivate Tgfbr2 in ECs after E10.5.…”

Section: Developmental Dynamicsmentioning

confidence: 99%

“…This permitted us to control the timing of endothelial Cre activity, and to inactivate Tgfbr2 in ECs after E10.5. Finally, following the unexpected finding that loss of Tgfbr2 expression in atrial and ventricular myocardium generated only a mild phenotype in cTnT-Cre/Tgfbr2fl/fl mice (Jiao et al, 2006), we sought to verify this phenotype using an independent ventricular myocardial-specific Cre line. For this experiment, we chose the Mlc2v-Cre mouse, in which Cre has been knocked into the Mlc2v locus, an early ventricular-restricted marker (Chen et al, 1998).…”

Section: Developmental Dynamicsmentioning

confidence: 99%

“…By using an inducible endothelial Cre to inactivate Tgfbr2, we were able to bypass the embryonic lethality at E10.5 to E11.5 caused by the constitutively expressed Tie2-Cre or Tie1-Cre lines (Jiao et al, 2006;Carvalho et al, 2007). We, therefore, activated Cre in ECs from E11.5, which also corresponds to the stage at which endothelial to mesenchymal transformation is almost complete.…”

Section: (Asterisk) Efmentioning

confidence: 99%

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The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

Robson

Allinson

Anderson

et al. 2010

Developmental Dynamics

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TGFb signalling is required for normal cardiac development. To investigate which cell types are involved, we used mice carrying a floxed Type II TGFb receptor (Tgfbr2fl) allele and Cre-lox genetics to deplete this receptor in different regions of the heart. The three target tissues and corresponding Cre transgenic lines were atrioventricular myocardium (using cGata6-Cre), ventricular myocardium (using Mlc2v-Cre), and vascular endothelium (using tamoxifen-activated Cdh5(PAC)-CreERT2). Spatio-temporal Cre activity in each case was tracked via lacZ activation from the Rosa26R locus. Atrioventricular-myocardial-specific Tgfbr2 knockout (KO) embryos had short septal leaflets of the tricuspid valve, whereas ventricular myocardial-specific KO embryos mainly exhibited a normal cardiac phenotype. Inactivation of Tgfbr2 in endothelial cells from E11.5 resulted in deficient ventricular septation, accompanied by haemorrhage from cerebral blood vessels. We conclude that TGFb signalling through the Tgfbr2 receptor, in endothelial cells, plays an important role in cardiac development, and is essential for cerebral vascular integrity. Developmental Dynamics 239:2435-2442,

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Section: (Asterisk) Efsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 90%

Section: Developmental Dynamicsmentioning

confidence: 99%

Section: Developmental Dynamicsmentioning

confidence: 99%

Section: (Asterisk) Efmentioning

confidence: 99%

See 3 more Smart Citations

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

Robson

Allinson

Anderson

et al. 2010

Developmental Dynamics

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ROCK1 Expression is Regulated by TGFβ3 and ALK2 During Valvuloseptal Endocardial Cushion Formation

Sakabe

Sakata

Matsui

et al. 2008

The Anatomical Record

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During early heart development at the looped heart stage, endothelial cells in the outflow tract and atrioventricular (AV) regions transform into mesenchyme to generate endocardial cushion tissue. This endocardial epithelial-mesenchymal transition (EMT) is regulated by several regulatory pathways, including the transforming growth factor-beta (TGFb), bone morphogenetic protein (BMP), and Rho-ROCK pathways. Here, we investigated the spatiotemporal expression pattern of ROCK1 mRNA during EMT in chick and examined whether TGFb or BMP could induce the expression of ROCK1. At the onset of EMT, ROCK1 expression was upregulated in endothelial/mesenchymal cells. A three-dimensional collagen gel assay was used to examine the mechanisms regulating the expression of ROCK1. In AV endocardium co-cultured with associated myocardium, ROCK1 expression was inhibited by either anti-TGFb3 antibody, anti-ALK2 antibody or noggin, but not SB431542 (ALK5 inhibitor). In cultured preactivated AV endocardium, TGFb3 protein induced the expression of ROCK1, but BMP did not. AV endothelial cells that were cultured in medium supplemented with TGFb3 plus anti-ALK2 antibody failed to express ROCK1. These results suggest that the expression of ROCK1 is up-regulated at the onset of EMT and that signaling mediated by TGFb3/ ALK2 together with BMP is involved in the expression of ROCK1. Anat Rec,

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TGFβ signaling and congenital heart disease: Insights from mouse studies

Arthur

Bamforth

2011

Birth Defects Research

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Transforming growth factor β (TGFβ) regulates one of the major signaling pathways that control tissue morphogenesis. In vitro experiments using heart explants indicated the importance of this signaling pathway for the generation of cushion mesenchymal cells, which ultimately contribute to the valves and septa of the mature heart. Recent advances in mouse genetics have enabled in vivo investigation into the roles of individual ligands, receptors, and coreceptors of this pathway, including investigation of the tissue specificity of these roles in heart development. This work has revealed that (1) cushion mesenchyme can form in the absence of TGFβ signaling, although mesenchymal cell numbers may be misregulated; (2) TGFβ signaling is essential for correct remodeling of the cushions, particularly those of the outflow tract; (3) TGFβ signaling also has a role in ensuring accurate remodeling of the pharyngeal arch arteries to form the mature aortic arch; and (4) mesenchymal cells derived from the epicardium require TGFβ signaling to promote their differentiation to vascular smooth muscle cells to support the coronary arteries. In addition, a mouse genetics approach has also been used to investigate the disease pathogenesis of Loeys-Dietz syndrome, a familial autosomal dominant human disorder characterized by a dilated aortic root, and associated with mutations in the two TGFβ signaling receptor genes, TGFBR1 and TGFBR2. Further important insights are likely as this exciting work progresses.

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Tgfβ signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development

Cited by 93 publications

References 38 publications

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

ROCK1 Expression is Regulated by TGFβ3 and ALK2 During Valvuloseptal Endocardial Cushion Formation

TGFβ signaling and congenital heart disease: Insights from mouse studies

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