The Transcription Factors c-rel and RelA Control Epidermal Development and Homeostasis in Embryonic and Adult Skin via Distinct Mechanisms

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Although the development of rela À/À c-rel À/À tnfa À/À embryos proceeds through to birth, newborn mice die within 12 h from unknown causes (Gugasyan et al, 2004). These mice are smaller than littermate controls but show no gross developmental defects.…”

“…In addition to a mild learning deficit (Meffert and Baltimore, 2005), loss of NF-kB p50/p105 function is associated with defects in stress responses, Hu et al (1999), Li et al (1999a), Takeda Grumont et al (1998Grumont et al ( , 1999, Cheng et al (2003), Pohl et al (2002) T cells: defects in CD4 and CD8 T-cell responses, Th1 development and cytokine production (IL-2 and GM-CSF) in CD4 + T-cell responses Hilliard et al (2002), Lamhamedi-Cherradi et al (2003), Mason et al (2004), Gerondakis et al (1996), Rao et al (2003) Horwitz et al (1997) rela À/À c-rel À/À Yes (BE13) Multiple hemopoietic defects. Radiation chimeras exhibit nucleated erythrocytes, reduced number of B cells, systemic expansion of granulocytes and a reduction in monocytes Grossmann et al (1999Grossmann et al ( , 2000 T cells exhibit a cell-cycle block early in G1 resulting from a failure to undergo c-Myc-dependent growth Grumont et al (2004) rela À/À c-rel À/ À tnf À/À Neonatal E18 embryos exhibit multiple epidermal defects that include a failure to form specific hair types, disorganized basal Gugasyan et al (2004) Knockout and transgenic models for NF-jB pathway S Gerondakis et al plus impaired innate and adaptive immune function. Ascribing the defects observed in nfkb1 À/À mice solely to a loss of p50 function is complicated by the finding that approximately one-third of the p105 pool acts as a scaffold for the MEK kinase Tpl2 (Beinke and Ley, 2004).…”

“…However, the recent findings that c-Rel is expressed at low levels in the epidermis and its appendages and is involved in epidermal keratinocyte function (Gugasyan et al, 2004) suggest that other non-hemopoietic functions for this transcription factor remain to be discovered.…”

“…These mice are smaller than littermate controls but show no gross developmental defects. A detailed analysis of development in rela À/À c-rel À/À tnfa À/À embryos has revealed that these transcription factors are essential for the normal development of epidermal structures (Gugasyan et al, 2004). In contrast to the normal skin structures seen in c-rel À/À tnfa À/À and rela À/À tnfa À/À mice, rela À/À c-rel À/À tnfa À/À embryos exhibit multiple epidermal defects that include a failure to form specific hair types, disorganized basal keratinocyte architecture and thinner skin.…”

“…With RelA expression being ubiquitous, the finding that c-Rel is normally expressed in hair follicle cells and basal layer keratinocytes, the same structures that are disrupted in the skin of rela À/À c-rel À/À tnfa À/À mice, indicates that the combined roles served by these transcription factors during skin differentiation are autonomous to these cells. In addition to these roles in embryonic skin, c-Rel and RelA control skin homeostasis in newborn mice by suppressing the recruitment and activation of the innate and adaptive immune systems (Gugasyan et al, 2004). This phenotype, which shares many features in common with the inflammatory skin conditions observed in mice with a keratinocyte-specific deletion of IKKb (Pasparakis et al, 2002a) or female mice heterozygous for an inactive allele of NEMO (Schmidt-Supprian et al, 2000), indicates that c-Rel and RelA appear to be the transcriptional mediators of this mechanism of immune suppression regulated by the IKKb/NEMO pathway.…”