Histology Atlas of the Developing Mouse Heart with Emphasis on E11.5 to E18.5

Savolainen, Saija M.; Foley, Julie F.; Elmore, Susan A.

doi:10.1177/0192623309335060

Cited by 141 publications

(141 citation statements)

References 64 publications

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“…This newly identified property of iASPP places it into a crucial position in the pathogenesis of ARVC. The heart undergoes a remodeling process during embryonic and early postnatal development, and this process requires proliferative and apoptotic signals (40). Neonatal cardiomyocytes do not form proper intercalated disc structures until day 15 of mouse postnatal development (41).…”

Section: Discussionmentioning

confidence: 99%

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Notari

Sutendra

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Desmosomes are anchoring junctions that exist in cells that endure physical stress such as cardiac myocytes. The importance of desmosomes in maintaining the homeostasis of the myocardium is underscored by frequent mutations of desmosome components found in human patients and animal models. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a phenotype caused by mutations in desmosomal components in ∼50% of patients, however, the causes in the remaining 50% of patients still remain unknown. A deficiency of inhibitor of apoptosis-stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves and Wa3 mice. However, the molecular mechanisms that mediate this putative function of iASPP are completely unknown. Here, we show that iASPP is expressed at intercalated discs in human and mouse postmitotic cardiomyocytes. iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks in vitro and in vivo. iASPP deficiency specifically induces right ventricular dilatation in mouse embryos at embryonic day 16.5. iASPPdeficient mice with exon 8 deletion (Ppp1r13l Δ8/Δ8 ) die of sudden cardiac death, displaying features of ARVC. Intercalated discs in cardiomyocytes from four of six human ARVC cases show reduced or loss of iASPP. ARVC-derived desmoplakin mutants DSP-1-V30M and DSP-1-S299R exhibit weaker binding to iASPP. These data demonstrate that by interacting with desmoplakin and desmin, iASPP is an important regulator of desmosomal function both in vitro and in vivo. This newly identified property of iASPP may provide new molecular insight into the pathogenesis of ARVC.ARVC | sudden death | desmosome | iASPP | cell-cell junctions

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Section: Discussionmentioning

confidence: 99%

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Notari

Sutendra

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Endothelial cells migrate out of the endothelium into the cardiac jelly to form cardiac cushions, which contribute to the formation of the cardiac valves and closure of the septum (Kisanuki et al, 2001;Savolainen et al, 2009;Webb et al, 1998) and affect the hemodynamics in the embryo, which could play a crucial role in the vascular remodeling process (Yashiro et al, 2007). However, whole-mount R26R-lacZ reporter staining of E10.5 and E11.5 5/v-cdKO embryos did not show any differences in cardiac cushion formation (see Fig.…”

Section: Research Articlementioning

confidence: 95%

Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development

et al. 2010

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SUMMARYIntegrin cell adhesion receptors and fibronectin, one of their extracellular matrix ligands, have been demonstrated to be important for angiogenesis using functional perturbation studies and complete knockout mouse models. Here, we report on the roles of the 5 and v integrins, which are the major endothelial fibronectin receptors, in developmental angiogenesis. We generated an integrin 5-floxed mouse line and ablated 5 integrin in endothelial cells. Unexpectedly, endothelial-specific knockout of integrin 5 has no obvious effect on developmental angiogenesis. We provide evidence for genetic interaction between mutations in integrin 5 and v and for overlapping functions and compensation between these integrins and perhaps others. Nonetheless, in embryos lacking both 5 and v integrins in their endothelial cells, initial vasculogenesis and angiogenesis proceed normally, at least up to E11.5, including the formation of apparently normal embryonic vasculature and development of the branchial arches. However, in the absence of endothelial 5 and v integrins, but not of either alone, there are extensive defects in remodeling of the great vessels and heart resulting in death at ~E14.5. We also found that fibronectin assembly is somewhat affected in integrin 5 knockout endothelial cells and markedly reduced in integrin 5/v double-knockout endothelial cell lines. Therefore, neither 5 nor v integrins are required in endothelial cells for initial vasculogenesis and angiogenesis, although they are required for remodeling of the heart and great vessels. These integrins on other cells, and/or other integrins on endothelial cells, might contribute to fibronectin assembly and vascular development.

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“…1D-G). In wild-type mice, cardiac septation is usually complete between E13.5 and E14.5 (Savolainen et al, 2009) (Fig. 1D).…”

Section: Sm22αmentioning

confidence: 97%

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

et al. 2015

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The RGD-binding α5 and αv integrins have been shown to be key regulators of vascular smooth muscle cell (vSMC) function in vitro. However, their role on vSMCs during vascular development in vivo remains unclear. To address this issue, we have generated mice that lack α5, αv or both α5 and αv integrins on their vSMCs, using the SM22α-Cre transgenic mouse line. To our surprise, neither α5 nor αv mutants displayed any obvious vascular defects during embryonic development. By contrast, mice lacking both α5 and αv integrins developed interrupted aortic arches, large brachiocephalic/ carotid artery aneurysms and cardiac septation defects, but developed extensive and apparently normal vasculature in the skin. Cardiovascular defects were also found, along with cleft palates and ectopically located thymi, in Wnt1-Cre α5/αv mutants, suggesting that α5 and αv cooperate on neural crest-derived cells to control the remodelling of the pharyngeal arches and the septation of the heart and outflow tract. Analysis of cultured α5/αv-deficient vSMCs suggests that this is achieved, at least in part, through proper assembly of RGD-containing extracellular matrix proteins and the correct incorporation and activation of latent TGF-β.

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Histology Atlas of the Developing Mouse Heart with Emphasis on E11.5 to E18.5

Cited by 141 publications

References 64 publications

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

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