NF-κB transmits Eda A1/EdaR signalling to activate Shh and cyclin D1 expression, and controls post-initiation hair placode down growth

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Abstract
A novel function of NF-κB in the development of most ectodermal appendages, including two types of murine pelage hair follicles, was detected in a mouse model with suppressed NF-κB activity (cIκBαΔN). However, the developmental processes regulated by NF-κB in hair follicles has remained unknown. Furthermore, the similarity between the phenotypes of cIκBAΔN mice and mice deficient in Eda A1 (tabby) or its receptor EdaR (downless) raised the issue of whether in vivo NF-κB regulates or is regulated by these novel TNF family members. We now demonstrate that epidermal NF-κB activity is first observed in placodes of primary guard hair follicles at day E14.5, and that in vivo NF-κB signalling is activated downstream of Eda A1 and EdaR. Importantly, ectopic signals which activate NF-κB can also stimulate guard hair placode formation, suggesting a crucial role for NF-κB in placode development. In downless and cIκBαΔN mice, placodes start to develop, but rapidly abort in the absence of EdaR/NF-κB signalling. We show that NF-κB activation is essential for induction of Shh and cyclin D1 expression and subsequent placode down growth. However, cyclin D1 induction appears to be indirectly regulated by NF-κB, probably via Shh and Wnt. The strongly decreased number of hair follicles observed in cIκBαΔN mice compared with tabby mice, indicates that additional signals, such as TROY, must regulate NF-κB activity in specific hair follicle subtypes.