The role of keratin 4 in mouse epithelial structure and function
Ness, Seth Lawrence
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The cytokeratins are cytoskeletal proteins in the intermediate filament family. Spanning the cell from the nucleus to desmosomes and hemidesmosomes, the keratins are traditionally thought to contribute to the structural integrity of the cell. The keratins are classified into two groups: the acidic type I keratins and the neutral-basic type II keratins. The keratin filament's basic unit is an obligate heteropolymer consisting of one type I and one type II molecule. These units interact in larger assemblies to form the cell-spanning strands.;There are at least 15 members of each group of keratins with more likely to be found. The particular pair of keratins that is expressed in a cell is characteristic of the tissue type. For example, keratins 5 and 14 are found in basal layers of stratified squamous epithelia and 4 and 13 are in suprabasal layers of non-keratinized stratified squamous epithelia.;Many studies have been done with the keratins of skin: 1, 5, 10 and 14. In addition, mice containing null mutations in K8, the keratin of simple epithelium and the early embryo, were generated by gene targeting methods. I chose to create a mouse containing a null mutation in keratin 4 to explore its function in non-keratinized stratified epithelia such as the oral mucosa and esophagus.;Mice containing a K4 null mutation display a specturm of phenotypes involving stratified epithelia. Histology revealed basal hyperplasia, lack of maturation, hyperkeratosis, atypical nuclei, perinuclear clearing and cell degeneration. Of particular interest is the basal hyperplasia which occurs in cells that do not themselves express keratin 4. These results suggest that the keratin network plays a role beyond that of imparting strength. Recently, two groups have linked the disease White Sponge Nevus of Cannon to dominant-negative mutations in K4 and its partner K13. The histological appearance of this disease is consistent with that of the K4 knockout mice.;In the course of my work I also identified a possible novel mouse type II keratin gene. This gene appears to lack the carboxy terminal domain of most other keratins and is expressed in skin.