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Erg is a crucial regulator of endocardial-mesenchymal transformation during cardiac valve morphogenesis.

Vijayaraj P, Le Bras A, Mitchell N, Kondo M, Juliao S, Wasserman M, Beeler D, Spokes K, Aird WC, Baldwin HS, Oettgen P - Development (2012)

Bottom Line: Four share a common translational start site encoded by exon 3 (Ex3) and are enriched in chondrocytes.The other three have a separate translational start site encoded by Ex4 and are enriched in endothelial cells.We show that Erg is required for the maintenance of the core EnMT regulatory factors that include Snail1 and Snail2 by binding to their promoter and intronic regions.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

ABSTRACT
During murine embryogenesis, the Ets factor Erg is highly expressed in endothelial cells of the developing vasculature and in articular chondrocytes of developing bone. We identified seven isoforms for the mouse Erg gene. Four share a common translational start site encoded by exon 3 (Ex3) and are enriched in chondrocytes. The other three have a separate translational start site encoded by Ex4 and are enriched in endothelial cells. Homozygous Erg(ΔEx3/ΔEx3) knockout mice are viable, fertile and do not display any overt phenotype. By contrast, homozygous Erg(ΔEx4/ΔEx4) knockout mice are embryonic lethal, which is associated with a marked reduction in endocardial-mesenchymal transformation (EnMT) during cardiac valve morphogenesis. We show that Erg is required for the maintenance of the core EnMT regulatory factors that include Snail1 and Snail2 by binding to their promoter and intronic regions.

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ErgΔEx4/ΔEx4 embryos display hemorrhages and disrupted vasculature. (A-D) Whole-mount images of Erg+/+ and ErgΔEx4/ΔEx4 mouse embryos at E10.5. ErgΔEx4/ΔEx4 embryos are growth retarded (B-D) and show hemorrhages (arrows in B-D) when compared with controls (A). (E,F) CD31 whole-mount immunohistochemistry of head of Erg+/+ (E) and ErgΔEx4/ΔEx4 (F) embryos at E10.5. (G-J) Magnified images of the boxed regions in E and F. Note the well-connected minor branches in the controls (G), whereas the mutants display a disorganized pattern of vasculature (H). (I) Wild-type embryo showing a segmented pattern of intersomitic vessels and capillary network, as compared with the severe disorganization of intersomitic vessels and reduced capillary network in ErgΔEx4/ΔEx4 embryos (J). (K,L) E10.5 ErgΔEx4/ΔEx4 embryo revealing pericardial effusion (K); the boxed region is magnified in L (arrow points to the effusion).
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Figure 7: ErgΔEx4/ΔEx4 embryos display hemorrhages and disrupted vasculature. (A-D) Whole-mount images of Erg+/+ and ErgΔEx4/ΔEx4 mouse embryos at E10.5. ErgΔEx4/ΔEx4 embryos are growth retarded (B-D) and show hemorrhages (arrows in B-D) when compared with controls (A). (E,F) CD31 whole-mount immunohistochemistry of head of Erg+/+ (E) and ErgΔEx4/ΔEx4 (F) embryos at E10.5. (G-J) Magnified images of the boxed regions in E and F. Note the well-connected minor branches in the controls (G), whereas the mutants display a disorganized pattern of vasculature (H). (I) Wild-type embryo showing a segmented pattern of intersomitic vessels and capillary network, as compared with the severe disorganization of intersomitic vessels and reduced capillary network in ErgΔEx4/ΔEx4 embryos (J). (K,L) E10.5 ErgΔEx4/ΔEx4 embryo revealing pericardial effusion (K); the boxed region is magnified in L (arrow points to the effusion).

Mentions: lacZ expression in ErgΔEx4/+ was seen throughout the entire vasculature of the embryo proper by E8.5-10.5 (3A-G) with particular accentuation of expression in the endocardium of the AVC. This pattern of lacZ expression was similar to the endothelial expression pattern that we reported previously by Erg immunohistochemistry in the developing mouse embryo (Nikolova-Krstevski et al., 2009). The homozygous ErgΔEx4/ΔEx4 embryos appeared smaller than heterozygous or Erg+/+ embryos by E9.5 (Fig. 5A,B). By E10.5, the embryos also displayed a significant reduction in size and exhibited hemorrhages in the head, trunk, or both regions (Fig. 5D; see Fig. 7A-D). These abnormalities were more striking in surviving embryos at E11.5, with marked reductions in the size and vascularization of ErgΔEx4/ΔEx4 embryos (Fig. 5F). No live ErgΔEx4/ΔEx4 embryos were observed beyond E11.5 (Table 1).


Erg is a crucial regulator of endocardial-mesenchymal transformation during cardiac valve morphogenesis.

Vijayaraj P, Le Bras A, Mitchell N, Kondo M, Juliao S, Wasserman M, Beeler D, Spokes K, Aird WC, Baldwin HS, Oettgen P - Development (2012)

ErgΔEx4/ΔEx4 embryos display hemorrhages and disrupted vasculature. (A-D) Whole-mount images of Erg+/+ and ErgΔEx4/ΔEx4 mouse embryos at E10.5. ErgΔEx4/ΔEx4 embryos are growth retarded (B-D) and show hemorrhages (arrows in B-D) when compared with controls (A). (E,F) CD31 whole-mount immunohistochemistry of head of Erg+/+ (E) and ErgΔEx4/ΔEx4 (F) embryos at E10.5. (G-J) Magnified images of the boxed regions in E and F. Note the well-connected minor branches in the controls (G), whereas the mutants display a disorganized pattern of vasculature (H). (I) Wild-type embryo showing a segmented pattern of intersomitic vessels and capillary network, as compared with the severe disorganization of intersomitic vessels and reduced capillary network in ErgΔEx4/ΔEx4 embryos (J). (K,L) E10.5 ErgΔEx4/ΔEx4 embryo revealing pericardial effusion (K); the boxed region is magnified in L (arrow points to the effusion).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 7: ErgΔEx4/ΔEx4 embryos display hemorrhages and disrupted vasculature. (A-D) Whole-mount images of Erg+/+ and ErgΔEx4/ΔEx4 mouse embryos at E10.5. ErgΔEx4/ΔEx4 embryos are growth retarded (B-D) and show hemorrhages (arrows in B-D) when compared with controls (A). (E,F) CD31 whole-mount immunohistochemistry of head of Erg+/+ (E) and ErgΔEx4/ΔEx4 (F) embryos at E10.5. (G-J) Magnified images of the boxed regions in E and F. Note the well-connected minor branches in the controls (G), whereas the mutants display a disorganized pattern of vasculature (H). (I) Wild-type embryo showing a segmented pattern of intersomitic vessels and capillary network, as compared with the severe disorganization of intersomitic vessels and reduced capillary network in ErgΔEx4/ΔEx4 embryos (J). (K,L) E10.5 ErgΔEx4/ΔEx4 embryo revealing pericardial effusion (K); the boxed region is magnified in L (arrow points to the effusion).
Mentions: lacZ expression in ErgΔEx4/+ was seen throughout the entire vasculature of the embryo proper by E8.5-10.5 (3A-G) with particular accentuation of expression in the endocardium of the AVC. This pattern of lacZ expression was similar to the endothelial expression pattern that we reported previously by Erg immunohistochemistry in the developing mouse embryo (Nikolova-Krstevski et al., 2009). The homozygous ErgΔEx4/ΔEx4 embryos appeared smaller than heterozygous or Erg+/+ embryos by E9.5 (Fig. 5A,B). By E10.5, the embryos also displayed a significant reduction in size and exhibited hemorrhages in the head, trunk, or both regions (Fig. 5D; see Fig. 7A-D). These abnormalities were more striking in surviving embryos at E11.5, with marked reductions in the size and vascularization of ErgΔEx4/ΔEx4 embryos (Fig. 5F). No live ErgΔEx4/ΔEx4 embryos were observed beyond E11.5 (Table 1).

Bottom Line: Four share a common translational start site encoded by exon 3 (Ex3) and are enriched in chondrocytes.The other three have a separate translational start site encoded by Ex4 and are enriched in endothelial cells.We show that Erg is required for the maintenance of the core EnMT regulatory factors that include Snail1 and Snail2 by binding to their promoter and intronic regions.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

ABSTRACT
During murine embryogenesis, the Ets factor Erg is highly expressed in endothelial cells of the developing vasculature and in articular chondrocytes of developing bone. We identified seven isoforms for the mouse Erg gene. Four share a common translational start site encoded by exon 3 (Ex3) and are enriched in chondrocytes. The other three have a separate translational start site encoded by Ex4 and are enriched in endothelial cells. Homozygous Erg(ΔEx3/ΔEx3) knockout mice are viable, fertile and do not display any overt phenotype. By contrast, homozygous Erg(ΔEx4/ΔEx4) knockout mice are embryonic lethal, which is associated with a marked reduction in endocardial-mesenchymal transformation (EnMT) during cardiac valve morphogenesis. We show that Erg is required for the maintenance of the core EnMT regulatory factors that include Snail1 and Snail2 by binding to their promoter and intronic regions.

Show MeSH
Related in: MedlinePlus