Keratins are the major structural protein of soft and hard epithelial cells. Type I (K9-K20; Ha1-Ha5) and TypeII (K1-K8; Hb1-Hb5) keratin sequences assemble into intermediate filaments as obligatory heteropolymers. Higher ordered filament complexes organize into a pan-cytoplasmic network interconnecting the nucleus to the surface of the cell. This complex network is a major determinant of the structural integrity in stratified epithelia. Most type I and type II keratin genes are expressed in a pairwise and differentiation specific fashion in epithelia. Keratin 6 (K6) is unique among mammalian type II keratins in that multiple isoforms have been identified in human, mouse, and bovine. Thus far in mice, the K6 isoforms appear to be differentially regulated; one is expressed constitutively while both are induced in response to a variety of challenges to the epidermis. Similarly, two of the six human K6 isoforms exhibit differential regulation while the others have yet to be fully characterized. The main objective of this proposal is to investigate the functional role of the multiple K6 isoforms in skin and other relevant epithelia in a mammalian organism. By using transgenic mouse models, the generation of null K6 mice along with gene replacement strategies will aid in deciphering the functional role, if any, of the K6alpha or K6beta proteins. The gene replacement experiments will also help examine the broader issue of the significance of having so many type II keratins. These studies will provide insight into keratin function during resting and challenged conditions in an in vivo context.
