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Abstract-The phenotypic hallmark of arrhythmogenic right ventricular cardiomyopathy, a genetic disease of desmosomal proteins, is fibroadipocytic replacement of the right ventricle. Cellular origin of excess adipocytes, the responsible mechanism(s) and the basis for predominant involvement of the right ventricle are unknown. We generated 3 sets of lineage tracer mice regulated by cardiac lineage promoters ␣-myosin heavy chain (␣MyHC), Nkx2.5, or Mef2C. We conditionally expressed the reporter enhanced yellow fluorescent protein while concomitantly deleting the desmosomal protein desmoplakin in cardiac myocyte lineages using the Cre-LoxP technique. Lineage tracer mice showed excess fibroadiposis and increased numbers of adipocytes in the hearts. Few adipocytes in the hearts of ␣MyHC-regulated lineage tracer mice, but the majority of adipocytes in the hearts of Nkx2.5-and Mef2C-regulated lineage tracer mice, expressed enhanced yellow fluorescent protein. In addition, rare cells coexpressed adipogenic transcription factors and the second heart field markers Isl1 and Mef2C in the lineage tracer mouse hearts and in human myocardium from patients with arrhythmogenic right ventricular cardiomyopathy. To delineate the responsible mechanism, we generated transgenic mice expressing desmosomal protein plakoglobin in myocyte lineages. Transgene plakoglobin translocated to nucleus, detected by immunoblotting and immunofluorescence staining and coimmunoprecipitated with Tcf7l2, a canonical Wnt signaling transcription factor. Expression levels of canonical Wnt/Tcf7l2 targets bone morphogenetic protein 7 and Wnt5b, which promote adipogenesis, were increased and expression level of connective tissue growth factor, an inhibitor of adipogenesis, was decreased. We conclude adipocytes in arrhythmogenic right ventricular cardiomyopathy originate from the second heart field cardiac progenitors, which switch to an adipogenic fate because of suppressed canonical Wnt signaling by nuclear plakoglobin. Key Words: adipocytes Ⅲ progenitor cells Ⅲ Wnt signaling Ⅲ desmosomes Ⅲ heart failure A rrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disease characterized by the unique phenotype of fibroadipocytic replacement of cardiac myocytes, predominantly in the right ventricle. [1][2][3] Clinical manifestations of ARVC include ventricular arrhythmias, typically originating from the right ventricle; sudden cardiac death, which often is its first manifestation; and right ventricular aneurysmal dilatation and failure. 1,4 The left ventricle is also commonly involved in the advanced stages. 1,5 ARVC is typically an autosomal dominant disease. Recessive forms in conjunction with palmoplantar keratoderma and woolly hair (Naxos disease) or predominant involvement of the left ventricle (Carvajal syndrome) are referred to as "cardiocutaneous syndromes." 6,7 Recently, mutations in 5 genes for ARVC, namely, DSP, JUP, PKP2, DSC2, and DSG2, encoding desmosomal proteins desmoplakin (Dsp), plakoglobin (PG), plakophilin 2, desmocollin 2, and ...

Loss of a sensory modality leads to widespread changes in synaptic function across sensory cortices, which are thought to be the basis for cross-modal adaptation. Previous studies suggest that experience-dependent cross-modal regulation of the spared sensory cortices may be mediated by changes in cortical circuits. Here, we report that loss of vision, in the form of dark exposure (DE) for 1 week, produces laminar-specific changes in excitatory and inhibitory circuits in the primary auditory cortex (A1) of adult mice to promote feedforward (FF) processing and also strengthens intracortical inputs to primary visual cortex (V1). Specifically, DE potentiated FF excitatory synapses from layer 4 (L4) to L2/3 in A1 and recurrent excitatory inputs in A1-L4 in parallel with a reduction in the strength of lateral intracortical excitatory inputs to A1-L2/3. This suggests a shift in processing in favor of FF information at the expense of intracortical processing. Vision loss also strengthened inhibitory synaptic function in L4 and L2/3 of A1, but via laminar specific mechanisms. In A1-L4, DE specifically potentiated the evoked synaptic transmission from parvalbumin-positive inhibitory interneurons to principal neurons without changes in spontaneous miniature IPSCs (mIPSCs). In contrast, DE specifically increased the frequency of mIPSCs in A1-L2/3. In V1, FF excitatory inputs were unaltered by DE, whereas lateral intracortical connections in L2/3 were strengthened, suggesting a shift toward intracortical processing. Our results suggest that loss of vision produces distinct circuit changes in the spared and deprived sensory cortices to shift between FF and intracortical processing to allow adaptation.