Attenuation of Wnt/β-catenin activity reverses enhanced generation of cardiomyocytes and cardiac defects caused by the loss of emerin

Abstract

Mutations in EMD, encoding emerin cause skeletal muscle and heart defects in patients with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) but the underlying mechanisms leading to cardiac defects are poorly understood. Here, we investigated the role of emerin in controlling cardiomyocyte proliferation and cardiac remodeling and explored its function in regulation of the Wnt/β-catenin pathway. We observed a remarkable increase of cardiomyocytes in emerin-null adult mice accompanied with decreased numbers of multinucleated cells. Depletion of emerin in mouse ES cell-derived cardiomyocytes by shRNA caused hyperactivation of Wnt/β-catenin signaling, increased proliferation and abrogated timely cardiac differentiation. Likewise, emerin-null mice exhibited increased Wnt/β-catenin signaling, cardiac dysfunction and perturbed hypertrophic remodeling following pressure overload. Pharmacological inhibition of β-catenin normalized proliferation and differentiation of ES cell-derived cardiomyocytes while inactivation of a single allele of β-catenin efficiently rescued cardiac dysfunction in emerin-null mice. We conclude that emerin constrains β-catenin signaling in the heart providing tight control of cardiomyocyte numbers. Enhanced Wnt/β-catenin signaling seems to contribute to cardiac defects observed in X-EDMD. Hence, therapeutic inhibition of Wnt/β-catenin signaling might be beneficial for X-EDMD patients.

Cell Mechanosensitivity Is Enabled by the LINC Nuclear Complex

“…Its nuclear localization and minimal effects on cytoplasmic actin supports the idea that emerin’s role is in nuclear actin assembly [39]. Emerin also complexes with αcatenin, βcatenin and LINC complexes and plays a role in the export of nuclear βcatenin as the deletion of emerin increases βcatenin nuclear accumulation [40–43]. Further, emerin is phosphorylated by Src kinases upon mechanical stimulation, which leads to increased nuclear stiffness in a lamin A/C dependent manner [44].…”

“…Interestingly, Sun1 [130] as well as torsin A in C. elegans [131] have been associated with nucleoporin function that facilitate nuclear βcatenin import. The LINC binding partner emerin also associates with βcatenin but in contrast appears to promote nuclear βcatenin export from the nucleus [40, 43]. These findings suggest that these mechanoresponsive LINC complexes and their binding partners not only participate in βcatenin signaling but that their mechanically adaptive nature may also play a dynamic role in mechanically modulating βcatenin access to nuclear pore complexes to inform MSC phenotype selection.…”

Causes and consequences of nuclear envelope alterations in tumour progression

“…Emerin interacts with β-catenin and represses its activity through negative regulation of nuclear accumulation (Markiewicz et al, 2006). Loss of emerin results in β-catenin nuclear localization and hyperactivation (Markiewicz et al, 2006; Stubenvoll et al, 2015). Lamin A directly interacts with emerin and is required for its NE localization, and lamin A/C has also been identified in complex with β-catenin (Bermeo et al, 2015; Vaughan et al, 2001).…”

Messages from the voices within: regulation of signaling by proteins of the nuclear lamina

“…MAN1 also might provide a scaffold for phosphatase-mediated inactivation of Smads [47]. Emerin has been shown to negatively regulate Wnt/β-catenin signaling by a related mechanism [10,48,49]. Activation of Wnt signaling involves the stabilization of β-catenin in the cytoplasm, and this promotes its nuclear accumulation and binding to gene promoters.…”

“…Mounting evidence from pharmacological and genetic analysis of mouse models indicates that many of these signaling perturbations may contribute to disease pathogenesis [5,6,7 •• ,8–10]. Understanding the molecular basic for these aberrations, and more generally, the role of NL proteins in regulating signal transduction, is a central challenge for the field.…”