Edd, the Murine Hyperplastic Disc Gene, Is Essential for Yolk Sac Vascularization and Chorioallantoic Fusion

Abstract

EDD is the mammalian ortholog of the Drosophila melanogaster hyperplastic disc gene (hyd), which is critical for cell proliferation and differentiation in flies through regulation of hedgehog and decapentaplegic signaling. Amplification and overexpression of EDD occurs frequently in several cancers, including those of the breast and ovary, and truncating mutations of EDD are also observed in gastric and colon cancer with microsatellite instability. EDD has E3 ubiquitin ligase activity, is involved in regulation of the DNA damage response, and may control hedgehog signaling, but a definitive biological role has yet to be established. To investigate the role of Edd in vivo, gene targeting was used to generate Edd knockout (Edd ⌬/⌬ ) mice. While heterozygous mice had normal development and fertility, no viable Edd-deficient embryos were observed beyond E10.5, with delayed growth and development evident from E8.5 onward. Failed yolk sac and allantoic vascular development, along with defective chorioallantoic fusion, were the primary effects of Edd deficiency. These extraembryonic defects presumably compromised fetal-maternal circulation and hence efficient exchange of nutrients and oxygen between the embryo and maternal environment, leading to a general failure of embryonic cell proliferation and widespread apoptosis. Hence, Edd has an essential role in extraembryonic development.

Modulation of Myocardin Function by the Ubiquitin E3 Ligase UBR5

“…In these mice vascular endothelial cell differentiation and organization were unaffected as determined by platelet endothelial cell adhesion molecule staining. Coincidently, the phenotype of UBR5 knock-out mice is very similar to the phenotype of myocardin knock-out mice (20). UBR5 null mouse embryos also died on E10.5 and showed defective yolk sac vascularization demonstrating a critical role for UBR5 in vascular development.…”

“…UBR5 has also been identified as a co-activator of progesterone receptor and potentiated progestin-mediated gene transactivation independent of its E3 ligase activity (21). More importantly, UBR5 null mouse embryos died by E10.5 and exhibited defective yolk sac vascularization (20), suggesting that UBR5 plays a critical role on vascular development. In the current study we identified UBR5 as a myocardin-binding protein and revealed an unexpected role for the ubiquitin E3 ligase UBR5 as an activator of smooth muscle differentiation through its ability to stabilize myocardin protein.…”

“…Near to the COOH-terminal HECT domain, UBR5 contains a poly(A)-binding protein domain, to bind with Paip2 and degrade it through ubiquitination (16). Recently studies have shown that UBR5 is involved in DNA repair (17,18), cancer progression (19), and mouse yolk sac vasculature network development (20). UBR5 has also been identified as a co-activator of progesterone receptor and potentiated progestin-mediated gene transactivation independent of its E3 ligase activity (21).…”

Deficiency of Zonula Occludens-1 Causes Embryonic Lethal Phenotype Associated with Defected Yolk Sac Angiogenesis and Apoptosis of Embryonic Cells

“…The restriction of the apoptotic area contrasted to the case of Edd-and connexin-45-deficient mice in which apoptosis occurred almost everywhere in embryos (at E9.5) indirectly caused by extraembryonic defects in angiogenesis. As well, reports on similar phenotypes (Goh et al, 1997;Radice et al, 1997;Kruger et al, 2000;Saunders et al, 2004;Argraves and Drake, 2005;Baumer et al, 2006;Morin-Kensicki et al, 2006;Dominguez et al, 2007) might possibly provide some clues about the mechanistic bases for the phenotypes in Tjp1 Ϫ/Ϫ mice. In the Drosophila tracheal system, the Drosophila homologue of ZO-1, Polychaetoid, is suggested to be involved in AJ remodeling in epithelial morphogenesis, partially consistent with our findings in embryonic and extraembryonic regions (Jung et al, 2006).…”

“…Accumulated cases report that defects in the visceral yolk sac and allantois lead to retarded growth of the embryo and early lethality because of defective blood circulation (Radice et al, 1997;Kruger et al, 2000;Rossant and Cross, 2001;Copp, 1995;Saunders et al, 2004); both of which were defective features in Tjp1 Ϫ/Ϫ embryos. It is noteworthy that the phenotypically related factors were VCAM-1, ␣ 4 -, ␣ 5 -integrin, connexin-45, VEcadherin, and N-cadherin, which were possibly related to cellcell interactions (Kwee et al, 1995;Yang et al, 1995;Goh et al, 1997;Radice et al, 1997;Gory-Faure et al, 1999;Kruger et al, 2000).…”