Abstract
Desmosome components are frequently mutated in cardiac and cutaneous disorders in animals and humans and enhanced inflammation is a common feature of these diseases. Previous studies showed that inhibitor of Apoptosis Stimulating p53 Protein (iASPP) regulates desmosome integrity at cell–cell junctions and transcription in the nucleus, and its deficiency causes cardiocutaneous disorder in mice, cattle, and humans. As iASPP is a ubiquitously expressed shuttling protein with multiple functions, a key question is whether the observed cardiocutaneous phenotypes are caused by loss of a cell autonomous role of iASPP in cardiomyocytes and keratinocytes specifically or by a loss of iASPP in other cell types such as immune cells. To address this, we developed cardiomyocyte-specific and keratinocyte-specific iASPP-deficient mouse models and show that the cell-type specific loss of iASPP in cardiomyocytes or keratinocytes is sufficient to induce cardiac or cutaneous disorders, respectively. Additionally, keratinocyte-specific iASPP-deficient mice have delayed eyelid development and wound healing. In keratinocytes, junctional iASPP is critical for stabilizing desmosomes and iASPP deficiency results in increased and disorganized cell migration, as well as impaired cell adhesion, consistent with delayed wound healing. The identification of a cell autonomous role of iASPP deficiency in causing cardiocutaneous syndrome, impaired eyelid development and wound healing suggests that variants in the iASPP gene also may contribute to polygenic heart and skin diseases.
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Acknowledgements
We would like to thank Indrika Ratnayaka for tissue sectioning, Mark Shipman for technical assistance with microscopy, Leonie Diffley (University of Manchester) for assisting with the MRI experiments, Guillermina Lozano (MD Anderson Cancer Center) for the p53 knockout mice, and Mary Muers for critical reading of the manuscript. This work was predominantly funded by the Ludwig Institute for Cancer Research (LICR) Ltd. J.E.S. is a BHF senior Basic Science Research Fellow (FS/11/50/29038), and acknowledges a Welcome Trust Core Award (090532/Z/09/Z). G.S. acknowledges support from Alberta Innovates Health Solutions.
Author Contributions
Z.D., G.S. and X.L. designed the experiments, analyzed data and wrote the paper. Y.H. initiated junctional iASPP study in keratinocytes. The myocardial-specific iASPP-deficient mice were generated and maintained by E.A.S. and G.S., and the epidermis-specific iASPP-deficient mice by K. C. and Z.D. Figure contributions: Z.D.—1A, B, D; 3; 4B, C, D, F; 5; S1A, S1D; S3; S4B–E; S5, G.S.—1A; 2B; S1C; S2B, Y.H.—4B, 4E, K. C.—1C; 5A-B; S1B; S5A-B, E.A.S.—1C; 2A; S2A, M.J.W.—S1C, F.Y.Z.—S4C; S5F, R.D.G.—S1C, D.J.P.F.—4A; S4A, D.M.—2B, J.E.S.—2B, D.M. and J.E.S. performed and analyzed the experiments in 2B. X.L. supervised the work and provided the funding for the study. All authors edited and approved the manuscript.
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MRI imaging in the orthogonal plane shows representative cardiac function of a myocardial-specific iASPP-deficient mouse with compromised cardiac function of both the RV and LV
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Dedeić, Z., Sutendra, G., Hu, Y. et al. Cell autonomous role of iASPP deficiency in causing cardiocutaneous disorders. Cell Death Differ 25, 1289–1303 (2018). https://doi.org/10.1038/s41418-017-0039-6
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DOI: https://doi.org/10.1038/s41418-017-0039-6
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