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Future research should unravel whether a gradual overall decay of transcriptional
capacity, whether or not caused by DNA lesions, underlies aspects of human aging .
Cys!ein·rich matrix
proteins (cuticle)
Cysteln-rich malJix
protelna (coI\ex)
High glycineltyrO$ine !emUn
Intanned/ate filament leralln
Hair Skin
......- Sll'atum oomeum
......- Gl8l'V.J1ar 18j6I"
(ioricrin, SPRR2)
......- Spinous lever
(K1,K10)
......- Besallajer
(Ks, K14)
Figure 3, Expression of differentiation specific genes in skin and hairfollicles. Within the epidermis,
proliferation takes place in the basal layer of hair and interfollicular keratinocytes that are attached to the
underlying basal membrane. Keratinocytes undergo terminal differentiation as they migrate through the
suprabasallayers, finally being shed from the tissue surface as dead cornified squarnes (skin, right) or
forming the hair fiber (left). In hair keratinocytes, the process of differentiation initiates a cascade of
keratin gene expression, in which consecutively the intermediate filaments, high glycine/tyrosine and
finally the cysteine-rich matrix proteins are expressed [51]. The specific reduction in CRP expression in
hair of TTD mice indicates a defect in a late stage of keratinocyte differentiation. Similarly,
interfollicular keratinocytes follow a process of terminal differentiation in which each distinct layer of
skin expresses a unique array of genes that produce characteristic differentiation products. The SPRR2
gene, encoding a structural component of the cornified envelope, is expressed in the granular layer,
which is the last stage before the cells dehydrate and enucleate to become squames. After Powell and
Rogers, 1994 [51] and Fuchs, 1995 [52] With permission, from the Annual Review of Cel1 and
Developmental Biology, volume 11 © 1995 by Annual Reviews.
CONCLUDING REMARKS AND FUTURE PERSPECTIVES
In recent years, an ever-growing series of NER-deficient mouse mutants has been
established. Until now these NER-deficient mice appear valid models for the human
syndromes with respect to a number of parameters such as genotoxic sensitivity, the
nature of the DNA repair defect, and carcinogenesis. Experimental mouse models
provide the opportnnity to investigate the role of DNA damage and NER in
processes like mutagenesis, apoptosis and immune suppression in vivo, and thus
establish the relative contribution of these phenomena in the multistep process of
carcinogenesis. In addition, some mouse mutants may contribute to increase
knowledge on the process of aging.
42 Chapter 2