title: 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 F(N)) functions as a hypomorph when combined with a null allele (PG Δ). About half of the PG F(N)/Δ animals were smaller than their littermates and died before weaning age, whereas the remaining PG F(N)/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 F(N)/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 F(N)/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.
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: David
authors.initials: D
authors.lastname: Swope
authors.forename: Jifen
authors.initials: J
authors.lastname: Li
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Muller
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Radice
mesh_terms: D000483:Alleles; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D006321:Heart / Q000033:anatomy & histology / Q000254:growth & development / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D051185:gamma Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D015820:Cadherins; C495293:Jup protein, mouse; D051176:beta Catenin; D051185:gamma Catenin