Limb and Skin Abnormalities in Mice Lacking IKKα

Abstract

The gene encoding inhibitor of kappa B (IkappaB) kinase alpha (IKKalpha; also called IKK1) was disrupted by gene targeting. IKKalpha-deficient mice died perinatally. In IKKalpha-deficient fetuses, limb outgrowth was severely impaired despite unaffected skeletal development. The epidermal cells in IKKalpha-deficient fetuses were highly proliferative with dysregulated epidermal differentiation. In the basal layer, degradation of IkappaB and nuclear localization of nuclear factor kappa B (NF-kappaB) were not observed. Thus, IKKalpha is essential for NF-kappaB activation in the limb and skin during embryogenesis. In contrast, there was no impairment of NF-kappaB activation induced by either interleukin-1 or tumor necrosis factor-alpha in IKKalpha-deficient embryonic fibroblasts and thymocytes, indicating that IKKalpha is not essential for cytokine-induced activation of NF-kappaB.

Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts

“…Consistent with such as model, targeted expression of IkBa m to the epidermis of transgenic mice leads to epithelial hyperplasia (Setiz et al, 1998), while expression of transgenes for constitutively nuclear p50 or RelA mutants leads to an inhibition of epithelial cell growth (Seitz et al, 1998). These ®ndings are consistent with the recent observation that IKKa-de®cient mice, which fail to activate Rel/NF-kB in epithelial cells also exhibit a block in epithelial cell di erentiation coupled with basal cell hyper-proliferation (Hu et al, 1999;Takeda et al, 1999).…”

“…Conservation of the vertebrate and invertebrate Rel/NF-kB pathways makes it highly likely that certain of the Dorsal-regulated genes important for embryonic pattern formation in¯ies will also be regulated by Rel/NF-kB in mammals. One such gene may be twist, the expression of which is reduced in ikka 7/7 embryos (Takeda et al, 1999). The skull and bone defects in ikka 7/7 mice resemble the phenotypes seen in mice heterozygous for a null allele of twist and in people su ering from Saethre-Chotzen syndrome, an autosomal dominant disorder arising from mutations in twist.…”

“…Despite the sequence similarity of IKKa and IKKb, the analysis of single knockout mice for these kinases has established that Rel/NF-kB activation by proinammatory cytokines is dependent largely on IKKb, whereas IKKa induces Rel/NF-kB during skin and skeletal development in response to an unidenti®ed morphogenetic signal(s). ikka 7/7 mice Mice homozygous for an ikka null mutation die post-natally, a icted with multiple morphological defects, the most striking of which is the encasement of the embryo in a shiny taut skin that prevents the emergence of fore-and hind-limbs (Hu et al, 1999;Takeda et al, 1999). Other defects include an absence of ears, truncation of the head and snout, and skeletal abnormalities a ecting the vertebrae, sternum, skull and digital phalanges that arise from the absence or inappropriate fusion of bones.…”

“…Nevertheless, evidence of a role for Rel/NF-kB factors in vertebrate limb and skin development has previously come from over-expressing mutant IkBa in chick embryos (Bushdid et al, 1998;Kanegae et al, 1998) and in the dermis of transgenic mice (Seitz et al, 1998). The normal induction of Rel/NF-kB in ikba 7/7 embryonic ®broblasts in response to the pro-inflammatory cytokines TNFa or IL-1 occurs via IKKb (Hu et al, 1999;Takeda et al, 1999), and this ®nding suggests that an unknown set of signals operating through IKKa is required for the induction of Rel/NFkB during skin and skeletal development.…”

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

“…The DNp51B-dominant condition achieved by targeting IKKa shows hyperplasia with concomitant increase of undifferentiated keratinocytes (Hu et al, 1999;Takeda et al, 1999). TAp51B transgenic mice suffer from epidermal hyperplasia and poor differentiation (Koster et al, 2004).…”