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

J Cell Sci. 2008 Jun 1;121(11):1887-98. doi: 10.1242/jcs.019075. Epub 2008 May 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Animals, Newborn
  • Cell Differentiation / physiology
  • Cell Nucleus / metabolism*
  • Cell Nucleus / ultrastructure
  • Cell Polarity / genetics
  • Cell Shape / genetics
  • Cells, Cultured
  • DNA Repeat Expansion / genetics
  • Epidermis / abnormalities
  • Epidermis / metabolism*
  • Epidermis / ultrastructure
  • Epithelial Cells / metabolism*
  • Epithelial Cells / ultrastructure
  • Fibroblasts / metabolism
  • Fibroblasts / ultrastructure
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / ultrastructure
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Mutation / genetics
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Envelope / metabolism*
  • Nuclear Envelope / ultrastructure
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary / genetics


  • Membrane Proteins
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Protein Isoforms
  • SYNE2 protein, human
  • emerin