Analysis of a Jup hypomorphic allele reveals a critical threshold for postnatal viability

Abstract

Mutations in the human Jup gene cause arrhythmogenic right ventricular cardiomyopathy (ARVC) a heart muscle disease that often leads to sudden cardiac death. Inactivation of the murine Jup gene (also known as plakoglobin) results in embryonic lethality due to cardiac rupture. In an effort to generate a conditional knockout allele, a neomycin cassette was introduced into the murine plakoglobin (PG) gene. This allele (PG FN) functions as a hypomorph when combined with a null allele (PG Δ). About half of the PG FN/Δ animals were smaller than their littermates and died before weaning age, whereas the remaining PG FN/Δ animals survived. Despite the reduced levels of PG in the heart, there were no signs of cardiomyopathy or cardiac dysfunction as determined by echocardiography. Importantly, the PG homolog, β-catenin (CTNNB1), was increased in the PG FN/Δ hearts. In addition to its structural role as part of the N-cadherin/catenin adhesion complex, β-catenin is a downstream effector of Wnt signaling. However, no change in β-catenin/TCF reporter activity was observed in PG FN/Δ embryos suggesting that excess β-catenin was not likely causing increased transcription of Wnt/β-catenin target genes. These data suggest novel function(s) for PG beyond the heart and define a critical threshold of PG expression that is necessary for postnatal survival.

Arrhythmogenic Cardiomyopathy

“…However, when expressing mutant forms of either PKP2 or JUP, cells exhibited abnormal signaling in response to mechanical stress, but showed a preserved intercellular adhesion, thus questioning a primary role of cell-cell adhesion in AC pathogenesis [92]. At the same time, Asimaki et al [93] demonstrated that a reduced junctional signal for JUP appears to be a hallmark of the disease in myocardial samples from AC patients, pointing to its possible role in intracellular signaling rather than adhesion, as suggested by other groups [94,95].…”

Beyond cell adhesion: The role of armadillo proteins in the heart

“…PG-deficient hearts have increase β-catenin [86] and vice versa [58]. Moreover, even reduction of PG as observed in PG hypomorph mice causes an increase in β-catenin levels [91]. The compensatory mechanism is posttranscriptional as no changes in β-catenin mRNA levels occur in these animal models [86, 91].…”

“…Moreover, even reduction of PG as observed in PG hypomorph mice causes an increase in β-catenin levels [91]. The compensatory mechanism is posttranscriptional as no changes in β-catenin mRNA levels occur in these animal models [86, 91]. Interestingly, despite the increase in β-catenin in the PG mutant mice there does not appear to be increased β-catenin transcriptional activity at least as determined by the β-catenin/TCF reporters, TOP-gal or Bat-gal [88, 91].…”

“…The compensatory mechanism is posttranscriptional as no changes in β-catenin mRNA levels occur in these animal models [86, 91]. Interestingly, despite the increase in β-catenin in the PG mutant mice there does not appear to be increased β-catenin transcriptional activity at least as determined by the β-catenin/TCF reporters, TOP-gal or Bat-gal [88, 91]. The inability of PG to support hypertrophic growth in the stressed myocardium of β-catenin CKO mice is consistent with its weaker transcriptional activity.…”

Normalization of Naxos plakoglobin levels restores cardiac function in mice

“…The lack of cardiac phenotype is not too surprising when understood in the context of the progression of Naxos disease, in which cardiac phenotype is age dependent (2). OriNax mutant perinatal lethality has also been observed in 50% of mice that are hypomorphic for WT plakoglobin, expressing approximately 40% of normal levels of WT plakoglobin (14). Perinatal lethality has not been reported for patients with Naxos disease.…”