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First published online 13 May 2008
doi: 10.1242/jcs.019075

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Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin

Yvonne Lüke^1,*, Hafida Zaim^1,*, Iakowos Karakesisoglou^1,2,*, Verena M. Jaeger¹, Lorenz Sellin³, Wenshu Lu¹, Maria Schneider¹, Sascha Neumann^1,4, Asa Beijer¹, Martina Munck^1,4, V. C. Padmakumar^1,4, Joachim Gloy³, Gerd Walz³ and Angelika A. Noegel^1,4,

¹ Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Cologne, Germany
² Department of Biological Sciences, The School of Biological and Biomedical Sciences, The University of Durham, Durham DH1 3LE, UK
³ Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany
⁴ Center for Molecular Medicine Cologne (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 52, 50931 Cologne, Germany

Author for correspondence (e-mail: Noegel{at}uni-koeln.de)

Accepted 20 March 2008

Giant isoforms, encoded by Nesprin-1 (Syne1) and Nesprin-2 (Syne2), are multifunctional actin-binding and nuclear-envelope-associated proteins belonging to the spectrin superfamily. Here, we investigate the function of Nesprin-2 Giant (NUANCE) in skin by generating mice lacking the actin-binding domain of Nesprin-2 (Nesprin-2ABD). This loss results in a slight but significant thickening of the epidermis, which is a consequence of the increased epithelial nuclear size. Nonetheless, epidermal proliferation and differentiation appear normal in the knockout epidermis. Surprisingly, Nesprin-2 C-terminal-isoform expression and nuclear envelope localization were affected in certain tissues. Nuclei of primary dermal knockout fibroblasts and keratinocytes were heavily misshapen, displaying a striking similarity to nuclear deformations characteristic of laminopathies. Furthermore, emerin, the protein involved in the X-linked form of Emery-Dreifuss muscular dystrophy (EDMD), was unevenly distributed along the nuclear envelope in mutant fibroblasts, often forming aggregates in the deformed nuclear envelope areas. Thus, Nesprin-2 is an important scaffold protein implicated in the maintenance of nuclear envelope architecture. Aged knockout fibroblasts readily generated, by alternative splicing and alternative translation initiation, aberrant Nesprin-2 Giant isoforms that lacked an ABD but that were sufficient to restore nuclear shape and emerin localization; this suggests that other regions of Nesprin-2 Giant, potentially including its spectrin repeats, are crucial for these functions.

Key words: KASH-domain, Mouse knockout, Laminopathies, Nuclear shape, Cell migration, Cell polarity

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