A single epithelial cell may produce multiple types of keratins, and these copolymerize into a single network (Figure 16–68). Keratin filaments impart mechanical strength to epithelial tissues in part by anchoring the intermediate filaments at sites of cell–cell contact, called desmosomes, or cell–matrix contact, called hemidesmosomes (see Figure 16–4). We discuss these important adhesive structures in Chapter 19. Accessory proteins, such as filaggrin, bundle keratin filaments in differentiating cells of the epidermis to give the outermost layers of the
Figure 16–68 Keratin filaments in epithelial cells. Immunofluorescence micrograph of the network of keratin filaments (blue) in a sheet of epithelial cells in culture. The filaments in each cell are indirectly connected to those of its neighbors by desmosomes (discussed in Chapter 19). A second protein (red) has been stained to reveal the location of the cell boundaries. (Courtesy of Kathleen Green and Evangeline Amargo.) skin their special toughness. Individuals with mutations in the gene encoding filaggrin are strongly predisposed to dry skin diseases such as eczema.
Mutations in keratin genes cause several human genetic diseases. For example, when defective keratins are expressed in the basal cell layer of the epidermis, they produce a disorder called epidermolysis bullosa simplex, in which the skin blisters in response to even very slight mechanical stress, which ruptures the basal cells (Figure 16–69). Other types of blistering diseases, including disorders of the mouth, esophageal lining, and the cornea of the eye, are caused by mutations in the different keratins whose expression is specific to those tissues. All of these maladies are typified by cell rupture as a consequence of mechanical trauma and a disorganization or clumping of the keratin filament cytoskeleton. Many of the specific mutations that cause these diseases alter the ends of the central rod domain, demonstrating the importance of this particular part of the protein for correct filament assembly.
Members of another family of intermediate filaments, called neurofilaments, are found in high concentrations along the axons of vertebrate neurons (Figure 16–70). Three types of neurofilament proteins (NF-L, NF-M, and NF-H) coassemble in vivo, forming heteropolymers. The NF-H and NF-M proteins have lengthy C-terminal tail domains that bind to neighboring filaments, generating aligned arrays with a uniform interfilament spacing. During axonal growth, new neurofilament subunits are incorporated all along the axon in a dynamic process that involves the addition of subunits along the filament length as well as the ends. After an axon has grown and connected with its target cell, the diameter of the axon may increase as much as fivefold. The level of neurofilament gene expression seems to directly control axonal diameter, which in turn influences how fast electrical signals travel down the axon. In addition, neurofilaments provide strength and stability to the long cell processes of neurons.
The neurodegenerative disease amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) is associated with an accumulation and abnormal assembly of neurofilaments in motor neuron cell bodies and in the axon, aberrations that may interfere with normal axonal transport. The degeneration of the axons leads to muscle weakness and atrophy, which is usually fatal. The overexpression of human NF-L or NF-H in mice results in mice that have an ALS-like disease. However, a causative link between neurofilament pathology and ALS has not been firmly established.
basal cell of epidermis