Figure 16–69 blistering of the skin caused by a mutant keratin gene. A mutant gene encoding a truncated keratin protein (lacking both the Nand C-terminal domains) was expressed in a transgenic mouse. The defective protein assembles with the normal keratins and thereby disrupts the keratin filament network in the basal cells of the skin. Light micrographs of cross sections of (A) normal and (B) mutant skin show that the blistering results from the rupturing of cells in the basal layer of the mutant epidermis (short red arrows). (C) A sketch of three cells in the basal layer of the mutant epidermis, as observed by electron microscopy. As indicated by the red arrow, the cells rupture between the nucleus and the hemidesmosomes (discussed in Chapter 19), which connect the keratin filaments to the underlying basal lamina. (From P.A. Coulombe et al., J. Cell Biol. 115:1661–1674, 1991. With permission from The Rockefeller University Press.)
The vimentin-like filaments are a third family of intermediate filaments. Desmin, a member of this family, is expressed in skeletal, cardiac, and smooth muscle, where it forms a scaffold around the Z disc of the sarcomere (see Figure 16–34). Mice lacking desmin show normal initial muscle development, but adults have various muscle-cell abnormalities, including misaligned muscle fibers. In humans, mutations in desmin are associated with various forms of muscular dystrophy and cardiac myopathy, illustrating the important role of desmin in stabilizing muscle fibers.
Besides their well-established role in maintaining the mechanical stability of the nucleus, it is becoming increasingly evident that one class of lamins, the A-type, together with many proteins of the nuclear envelope, are scaffolds for proteins that control myriad cellular processes including transcription, chromatin organization, and signal transduction. The majority of laminopathies are associated with mutant versions of lamin A and include tissue-specific diseases. Skeletal and cardiac abnormalities might be explained by a weakened nuclear envelope leading to cell damage and death, but laminopathies are also thought to arise from pathogenic and tissue-specific alterations in gene expression.
Linker Proteins Connect Cytoskeletal Filaments and Bridge the Nuclear Envelope
The intermediate filament network is linked to the rest of the cytoskeleton by members of a family of proteins called plakins. Plakins are large and modular, containing multiple domains that connect cytoskeletal filaments to each other and to junctional complexes. Plectin is a particularly interesting example. In addition to bundling intermediate filaments, it links the intermediate filaments to microtubules, actin filament bundles, and filaments of the motor protein myosin II; it also helps attach intermediate filament bundles to adhesive structures at the plasma membrane (Figure 16–71).
Plectin and other plakins can interact with protein complexes that connect the cytoskeleton to the nuclear interior. These complexes consist of SUN proteins 0.5 µm
Figure 16–70 Two types of intermediate filaments in cells of the nervous system.
Freeze-etch electron microscopic image of neurofilaments in a nerve cell axon, showing the extensive cross-linking through protein cross-bridges—an arrangement believed to give this long cell process great tensile strength. The cross-bridges are formed by the long, nonhelical extensions at the C-terminus of the largest neurofilament protein (NF-H). (B) Freeze-etch image of glial filaments in glial cells, showing that these intermediate filaments are smooth and have few cross-bridges.
Conventional transmission electron micrograph of a cross section of an axon showing the regular side-to-side spacing of the neurofilaments, which greatly outnumber the microtubules.  (A and B, courtesy of Nobutaka Hirokawa; C, courtesy of John Hopkins.)