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JCS ePress
online publication date 13 May 2008
doi: 10.1242/jcs.019075
Research Article
Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin
Yvonne Lüke,
Hafida Zaim,
Iakowos Karakesisoglou,
Verena M. Jaeger,
Lorenz Sellin,
Wenshu Lu,
Maria Schneider,
Sascha Neumann,
Asa Beijer,
Martina Munck,
V. C. Padmakumar,
Joachim Gloy,
Gerd Walz,
and
Angelika A. Noegel*
* Author for correspondence (e-mail: Noegel{at}uni-koeln.de)
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-2
ABD). 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.
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