Mutations in EDA, EDAR (EDA-receptor) and EDARADD (EDA-receptor associated death domain gene) or in their mouse homologs cause anhidrotic ectodermal dysplasia in man and mouse (Mikkola et al, 2003). Mutations in IKK-gamma cause incontinentia pigmenti and ectodermal dysplasia with immunodeficiency syndromes, presumably by inhibiting NF-kB-activity (Zonana et al, 2000; Döffinger et al, 2001). IKK-alfa null mutant mice die perinatally and have a shiny and taut skin with thickened, undifferentiated epidermis that presumably prevents the outgrowth of limbs (Ohazama et al, 2004).
IKK-alfa null mutant mice have also abnormal tooth development (Ohazama et al, 2004). Molars have shallow cusps resembling those in EDA, EDAR (EDA-receptor) and EDARADD mutants Tabby, downless, sleek and crinkled. The enamel knots of molars are also smaller than in normally. Incisors are shortened and their crowns are enlarged. Incisors are also exposed to oral cavity already at birth. Interestingly, in the early development of incisors as well as whiskers, the epithelium grows outwards instead of forming the normal epithelial bud by ingrowth. This is preceded by an enlargement of the area of expression of Sonic hedgehog (Shh) in the presumptive dental epithelium and retreat of the expression of Wnt7b from the area of expression of Shh. The expression of Notch1 is also downregulated in E13 and E14 incisor and molar epithelium but the expression of Notch2 only in incisor epithelium. However, incisor development and Notch expression were normal in mice with superrepressor form of IkB-alfa (Inhibitor of kB-alfa), suggesting that aberrant development of incisors and whiskers is not mediated by disturbing the NF-kB function.
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