Abstract
The Coxsackie virus and adenovirus receptor (CXADR) is an adhesion molecule known for its role in virus-cell interactions, epithelial integrity, and organogenesis. Loss of Cxadr causes numerous embryonic defects in mice, notably abnormal development of the cardiovascular system, and embryonic lethality. While CXADR expression has been reported in the placenta, the precise cellular localization and function within this tissue are unknown. Since impairments in placental development and function can cause secondary cardiovascular abnormalities, a phenomenon referred to as the placenta-heart axis, it is possible placental phenotypes in Cxadr mutant embryos may underlie the reported cardiovascular defects and embryonic lethality. In the current study, we determine the cellular localization of placental Cxadr expression and whether there are placental abnormalities in the absence of Cxadr. In the placenta, CXADR is expressed specifically by trophoblast labyrinth progenitors as well as cells of the visceral yolk sac (YS). In the absence of Cxadr, we observed altered expression of angiogenic factors coupled with poor expansion of trophoblast and fetal endothelial cell subpopulations, plus diminished placental transport. Unexpectedly, preserving endogenous trophoblast Cxadr expression revealed the placental defects to be secondary to primary embryonic and/or YS phenotypes. Moreover, further tissue-restricted deletions of Cxadr suggest that the secondary placental defects are likely influenced by embryonic lineages such as the fetal endothelium or those within the extraembryonic YS vascular plexus.
Highlights
The Coxsackie virus and adenovirus receptor (CXADR) was originally characterized as a viral receptor that enables both Coxsackie B virus and adenovirus serotypes to gain entry into host cells (Bergelson et al, 1997; Tomko et al, 1997)
At E10.5, CXADR protein localization was detected in the chorionic plate and again in small clusters throughout the labyrinth, and mRNA transcripts were identified in the outer epithelial layer of the visceral yolk sac (YS) (Figures 1B,C)
Since impairments in placental development and function can cause secondary cardiovascular abnormalities, a phenomenon referred to as the placenta-heart axis, we hypothesized that placental phenotypes may underlie or contribute to the reported cardiovascular defects and embryonic lethality observed in Cxadr mutant embryos
Summary
The Coxsackie virus and adenovirus receptor (CXADR) was originally characterized as a viral receptor that enables both Coxsackie B virus and adenovirus serotypes to gain entry into host cells (Bergelson et al, 1997; Tomko et al, 1997). CXADR has been recognized as a cell adhesion molecule, a component of apical junction complexes, and has been implicated in numerous physiological functions during embryonic development and epithelial cell interactions (Supplementary Table S1). Ubiquitous deletion of Cxadr is embryonic lethal between embryonic day (E) 11.5 and E13.5 with some null embryos variably reported to exhibit edema, hemorrhage, delayed heart development or valve formation, distended pericardia, enlarged aorta and cardinal veins, increased cardiomyocyte apoptosis, or proliferation (Asher et al, 2005; Dorner et al, 2005; Chen et al, 2006). Early cardiac defects associated with placental malformation have been shown to include smaller cardiac chambers, myocardial thinning, pericardial effusion, hemorrhage, increased cardiomyocyte apoptosis, ventricular septal defects, and missing atrioventricular cushions, some of which mirror those reported in the various Cxadr null studies (Barak et al, 1999; SchorppKistner et al, 1999a; Adams et al, 2000; Mudgett et al, 2000; Schreiber et al, 2000; Hatano et al, 2003; GalabovaKovacs et al, 2006; Raffel et al, 2008; Ouseph et al, 2012; Maruyama et al, 2016; Perez-Garcia et al, 2018)
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