What chick and mouse models have taught us about the role of the endocardium in congenital heart disease

DeLaughter, Daniel M.; Saint-Jean, Leshana; Baldwin, H. Scott; Barnett, Joey V.

doi:10.1002/bdra.20809

Cited by 34 publications

(39 citation statements)

References 173 publications

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“…We can observe MGP also in the trabeculae, which are formed in an event where endocardial cells participate (DeLaughter et al, 2011). Interestingly, in addition to the fact that it is expressed in a layer of endocardium that covers the interior of the heart, it is known that Notch intracellular domain (NICD) is also detected in other endocardial populations such as the atrium and ventricles (DeLaughter et al, 2011). This expression pattern seems to correlate with MGP's, which could be modulating Notch pathway in those tissues.…”

Section: In Some Regions Of the Atrium (Yellow Hastag) And In The Sinmentioning

confidence: 71%

“…Overall, this would indicate that MGP is being expressed by activated endothelial cells, being seen both in the endocardium and in the AVC. We can observe MGP also in the trabeculae, which are formed in an event where endocardial cells participate (DeLaughter et al, 2011). Interestingly, in addition to the fact that it is expressed in a layer of endocardium that covers the interior of the heart, it is known that Notch intracellular domain (NICD) is also detected in other endocardial populations such as the atrium and ventricles (DeLaughter et al, 2011).…”

Section: In Some Regions Of the Atrium (Yellow Hastag) And In The Sinmentioning

confidence: 90%

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Matrix Gla Protein expression pattern in the early avian embryo

Correia¹,

Conceição²,

Cancela³

et al. 2016

Int. J. Dev. Biol.

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MGP (Matrix Gla Protein) is an extracellular matrix vitamin K dependent protein previously identified as a physiological inhibitor of calcification and shown to be well conserved among vertebrates during evolution. MGP is involved in other mechanisms such as TGF-b and BMP activity, and a proposed modulator of cell-matrix interactions. MGP is expressed early in vertebrate development although its role has not been clarified. Previous work in the chicken embryo found MGP localization predominantly in the aorta and aortic valve base, but no data is available earlier in development. Here we examined MGP expression pattern using whole-mount in situ hybridization and histological sectioning during the initial stages of chick development. MGP was first detected at HH10 in the head and in the forming dorsal aorta. At the moment of the onset of blood circulation, MGP was expressed additionally in the venous plexus which will remodel into the vitelline arteries. By E2.25, it is clear that the vitelline arteries are MGP positive. MGP expression progresses centrifugally throughout the area vasculosa of the yolk sac. Between stages HH17 and HH19 MGP is seen in the dorsal aorta, heart, notochord, nephric duct, roof plate, vitelline arteries and in the yolk sac, beneath main arterial branches and in the vicinity of several vessels and venules. MGP expression persists in these areas at least until E4.5. These data suggest that MGP expression could be associated with cell migration and differentiation and to the onset of angiogenesis in the developing chick embryo. This data has biomedical relevance by pointing to the potential use of chick embryo explants to study molecules involved in artery calcification. KEY WORDS: MGP, angiogenesis, heart development, brain development, yolk sacMatrix Gla Protein (MGP) is a small secreted protein present in the extracellular matrix (ECM) that is known to be a physiological inhibitor of calcification. The correlation between the absence of functional MGP and aberrant calcification of both arteries and cartilage was clearly established following the development of the MGP knock-out mice (Luo et al., 1997). In humans, MGP mutations are the genetic basis of the Keutel syndrome (KS), a rare autosomal recessive disease characterized by abnormal cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenosis, hearing loss, and facial abnormalities (Keutel et al., 1971;Hur et al., 2005).Multiple functions have been associated to MGP. These functions include the regulation of calcium phosphate transport (Price et al., 2002), the activity of TGF-b1 (Bostrom et al., 2004), the inhibition of BMP2 (Wallin et al., 2000), BMP4, and BMP7 by direct binding Int. J. Dev. Biol. 60: 71-76 (2016) ( Yao et al., 2011), the maintenance of BMP and Notch signaling balance and the maintenance of normal endothelial cell function (Sharma and Albig, 2013;Yao et al., 2013).Nonetheless, MGP appears early in development, being expressed in a specific pattern in embryonic tissues, suggesting a...

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Section: In Some Regions Of the Atrium (Yellow Hastag) And In The Sinmentioning

confidence: 71%

Section: In Some Regions Of the Atrium (Yellow Hastag) And In The Sinmentioning

confidence: 90%

Matrix Gla Protein expression pattern in the early avian embryo

Correia¹,

Conceição²,

Cancela³

et al. 2016

Int. J. Dev. Biol.

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“…The regulation of EMT by members of the TGFβ family is a major component of heart valve [6, 7] and coronary vessel [8, 9] development. Formation of the coronary vessels begins when cells of the proepicardium attach to the heart to form the epicardium [8, 10–12].…”

Section: 0 Introductionmentioning

confidence: 99%

BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFβ receptor to promote invasion

Hill¹,

Sánchez²,

Love³

et al. 2012

Cellular Signalling

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Coronary vessel development depends on a subpopulation of epicardial cells that undergo epithelial to mesenchymal transformation (EMT) and invade the subepicardial space and myocardium. These cells form the smooth muscle of the vessels and fibroblasts, but the mechanisms that regulate these processes are poorly understood. Mice lacking the Type III Transforming Growth Factor β Receptor (TGFβR3) die by E14.5 due to failed coronary vessel development accompanied by reduced epicardial cell invasion. BMP2 signals via TGFβR3 emphasizing the importance of determining the relative contributions of the canonical BMP signaling pathway and TGFβR3-dependent signaling to BMP2 responsiveness. Here we examined the role of TGFβR3 in BMP2 signaling in epicardial cells. Whereas TGFβ induced loss of epithelial character and smooth muscle differentiation, BMP2 induced an ALK3-dependent loss of epithelial character and modestly inhibited TGFβ-stimulated differentiation. Tgfbr3−/− cells respond to BMP2 indicating that TGFβR3 is not required. However, Tgfbr3−/− cells show decreased invasion in response to BMP2 and overexpression of TGFβR3 in Tgfbr3−/− cells rescued invasion. Invasion was dependent on ALK5, ALK2, ALK3, and Smad4. Expression of TGFβR3 lacking the 3 C-terminal amino acids required to interact with the scaffolding protein GIPC (GAIP-interacting protein, C terminus) did not rescue. Knockdown of GIPC in Tgfbr3+/+ or Tgfbr3−/− cells rescued with TGFβR3 decreased BMP2-stimulated invasion confirming a requirement for TGFβR3/GIPC interaction. Our results reveal the relative roles of TGFβR3-dependent and TGFβR3-independent signaling in the actions of BMP2 on epicardial cell behavior and demonstrate the critical role of TGFβR3 in mediating BMP2-stimulated invasion.

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“…These properties of the endocardium allowed for the development of both loss- and gain-of-function assays to probe the receptor domains and downstream signals required for TGFβR3-mediated endothelial cell transformation (reviewed in [12]). Given that TGFβR3 also binds BMP-2 and induces endothelial cell transformation [13] this approach also allowed for the comparison of TGFβ and BMP signaling through TGFβR3 in mediating cell transformation.…”

Section: 0 Introductionmentioning

confidence: 99%

Endocardial cell epithelial-mesenchymal transformation requires Type III TGFβ receptor interaction with GIPC

Townsend¹,

Robinson²,

How³

et al. 2012

Cellular Signalling

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An early event in heart valve formation is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endothelial cells in specific regions of the heart tube, the endocardial cushions. The Type III TGFβ receptor (TGFβR3) is required for TGFβ2- or BMP-2-stimulated EMT in atrioventricular endocardial cushion (AVC) explants in vitro but the mediators downstream of TGFβR3 are not well described. Using AVC and ventricular explants as an in vitro assay, we found an absolute requirement for specific TGFβR3 cytoplasmic residues, GAIP-interacting protein, C terminus (GIPC), and specific Activin Receptor-Like Kinases (ALK)s for TGFβR3-mediated EMT when stimulated by TGFβ2 or BMP-2. The introduction of TGFβR3 into nontransforming ventricular endocardial cells, followed by the addition of either TGFβ2 or BMP-2, results in EMT. TGFβR3 lacking the entire cytoplasmic domain, or only the 3 C-terminal amino acids that are required to bind GIPC, fails to support EMT in response to TGFβ2 or BMP-2. Overexpression of GIPC in AVC endocardial cells enhanced EMT while siRNA-mediated silencing of GIPC in ventricular cells overexpressing TGFβR3 significantly inhibited EMT. Targeting of specific ALK’s by siRNA revealed that TGFβR3-mediated EMT requires ALK2 and ALK3, in addition to ALK5, but not ALK4 or ALK6. Taken together, these data identify GIPC, ALK2, ALK3, and ALK5 as signaling components required for TGFβR3-mediated endothelial cell EMT.

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What chick and mouse models have taught us about the role of the endocardium in congenital heart disease

Cited by 34 publications

References 173 publications

Matrix Gla Protein expression pattern in the early avian embryo

Matrix Gla Protein expression pattern in the early avian embryo

BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFβ receptor to promote invasion

Endocardial cell epithelial-mesenchymal transformation requires Type III TGFβ receptor interaction with GIPC

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