Abstract
The mouse hair coat comprises protective “primary” and thermo-regulatory “secondary” hairs. Primary hair formation is ectodysplasin (Eda) dependent, but it has been puzzling that Tabby (Eda -/y) mice still make secondary hair. We report that Dickkopf 4 (Dkk4), a Wnt antagonist, affects an auxiliary pathway for Eda-independent development of secondary hair. A Dkk4 transgene in wild-type mice had no effect on primary hair, but secondary hairs were severely malformed. Dkk4 action on secondary hair was further demonstrated when the transgene was introduced into Tabby mice: the usual secondary follicle induction was completely blocked. The Dkk4-regulated secondary hair pathway, like the Eda-dependent primary hair pathway, is further mediated by selective activation of Shh. The results thus reveal two complex molecular pathways that distinctly regulate subtype-based morphogenesis of hair follicles, and provide a resolution for the longstanding puzzle of hair formation in Tabby mice lacking Eda.
Highlights
Skin appendage formation is regulated by reciprocal signaling between mesenchyme and ectoderm, involving common morphogens such as Wnt, Shh and BMP [1]
Unlike primary hair follicle development that solely depends on Eda, we show that secondary hair follicle development is mainly regulated by a Dickkopf 4 (Dkk4)-regulated pathway; both pathways converge to mediate hair production through the Shh pathway
But secondary hairs were severely malformed in Dkk4 transgenic mice in wild-type background
Summary
Skin appendage formation is regulated by reciprocal signaling between mesenchyme and ectoderm, involving common morphogens such as Wnt, Shh and BMP [1]. For example, all scale formation depends on eda; and in mammals, sweat gland development shows a complete dependence on the EDA pathway [6,7]. In mice, ‘‘primary’’ guard hairs, constituting less than 5% of mouse hair on the back skin, overlay and protect the 95% of ‘‘secondary’’ hairs. Secondary hair, including awl, auchen and zigzag subtypes, have a pivotal physiological role as a thermal insulator, compensating for the lack of sweat glands on the mouse body. In Eda mutant Tabby mice, no primary hair follicles form, but secondary follicles initiate normally, though they result in straight, thin, short hairs [8,9]
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