Novel insights into intermediate-filament function from studies of transgenic and knockout mice

Abstract

The function of intermediate-filament (IF) proteins has been a matter of speculation for a long time. Now, the analysis of genetically altered mice is contributing to the understanding of their function. While the initial analysis of knockout mice supports the global view that keratins in epidermis and desmin in muscle serve an important structural function by protecting these tissues against mechanical stress, the detailed examination of these and other mice suggests that IF are more than passive cytoskeletal proteins. This is highlighted by mice with deficiencies for keratins in internal epithelia, vimentin, GFAP, or neurofilament proteins. These lack overt phenotypes expected as a result of cytoskeletal deficiency but show defects compatible with a role of IF in protecting tissues against toxic and other forms of stress. Moreover, the first round of gene replacement experiments suggests that keratins from internal epithelia are unable to take the place of their epidermal counterparts. The development of mice with point mutations, paralleled by the mutation analysis of human diseases and the characterization of IF-associated proteins will be instrumental to understand why evolution has produced such a diverse gene family to encode simple 10 nm diameter filaments.