Early studies of skeletal muscle revealed the existence of two kinds of protein filaments: thick, ∼150 Å–diameter myosin filaments and thin, ∼60 Å–diameter actin filaments. These filaments combine to form myofibrils in developing and mature muscle cells. The year 1968 brought the discovery of another class of filaments ∼100 Å in diameter (Ishikawa et al., 1968). These intermediate filaments constitute the majority of free filaments in the cytoplasm of most eukaryotic cells.
“There were many reports of free, thin cytoplasmic filaments in many kinds of cells. At the time, these were generally thought to be actin,” says Howard Holtzer. “We thought that they might be a completely new kind of filament because of their failure to be decorated with heavy meromyosin. And, unlike actin, they were of indefinite lengths.”
Earlier experiments by Inoué (1952) and Tilney (1965) had shown that the mitotic inhibitor colchicine caused depolymerization of another set of protein fibers found in most cells, the microtubules. When Holtzer and colleagues reared any of a wide variety of cells in colchicine, they noted that as the microtubules disappeared, the individual cytoplasmic filaments aggregated laterally into “immense, meandering, translucent cables,” says Holtzer. When the colchicine was washed out, the cables disassembled into their constituent filaments. Colchicine, however, had no obvious effects on the maturing actin filaments of the myofibrils.
By measuring the diameter of individual filaments by electron microscopy, Holtzer and colleagues were able to determine that the free cytoplasmic filaments, and those in the cochicine-induced cables, had a diameter different from that of actin filaments. These filaments were named “intermediate filaments” because their size was between that of myosin and actin filaments in muscle cells.
The 1968 study was followed by an explosion of research that quickly lead to the identification of many intermediate filament isoforms, such as the nuclear lamins, vimentin-like filaments, keratins, and neurofilaments. Many of these give mechanical stability to cells (Janmey et al., 1991), but some, says Holtzer, “are almost certain to be involved in cell differentiation and cell maturation.” Changes in the state of their aggregation following stress, infection, or mutation are diagnostic of specific human diseases, and their varied expression profiles in different epithelia make them particularly useful in classifying the tissue of origin of many tumors.