title: Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin.
abstract: 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-2DeltaABD). 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.
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lüke
authors.forename: Hafida
authors.initials: H
authors.lastname: Zaim
authors.forename: Iakowos
authors.initials: I
authors.lastname: Karakesisoglou
authors.forename: Verena M
authors.initials: VM
authors.lastname: Jaeger
authors.forename: Lorenz
authors.initials: L
authors.lastname: Sellin
authors.forename: Wenshu
authors.initials: W
authors.lastname: Lu
authors.forename: Maria
authors.initials: M
authors.lastname: Schneider
authors.forename: Sascha
authors.initials: S
authors.lastname: Neumann
authors.forename: Asa
authors.initials: A
authors.lastname: Beijer
authors.forename: Martina
authors.initials: M
authors.lastname: Munck
authors.forename: V C
authors.initials: VC
authors.lastname: Padmakumar
authors.forename: Joachim
authors.initials: J
authors.lastname: Gloy
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Angelika A
authors.initials: AA
authors.lastname: Noegel
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D016764:Cell Polarity / Q000235:genetics; D048430:Cell Shape / Q000235:genetics; D002478:Cells, Cultured; D042622:DNA Repeat Expansion / Q000235:genetics; D004817:Epidermis / Q000002:abnormalities / Q000378:metabolism* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C485904:SYNE2 protein, human; C092710:emerin