Hair follicle development: induction - stage 1 of 3 (Homo sapiens)
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Induction
Mesenchymal Wnt as the first signal
In hair follicle (HF) development, the induction stage marks the beginning of the crosstalk between epithelium and mesenchyme (represented at Figure 1A as yellow and blue cell compartments, respectively). The first compartment will result in the small focal epithelial thickening, named placode, which, later, will give origin to most of the layers of the HF. Then, the second cell compartment results in the dermal condensate, which thereafter becomes the dermal papilla [16–18]. The first signal for induction is given by mesenchymal cells expressing WNT (Figure 1A middle left) early in development [17,19–21]. Although it is not known what specific Wnt is responsible for this first signal, some authors consider Wnt10b as a reasonable candidate [22]. Anyhow, activation of Wnt signaling pathway blocks β-catenin cytoplasmic degradation fate, releasing this transcription factor to get in the nucleus and starts expression of placode formation genes. During embryogenesis, β-catenin in the HF epithelium, together with two transcription factors, Lef1 and Tcf3-4 [21], is capable of activating the expression of several crucial genes for HF induction and morphogenesis. Between them are MYC, SP5, DKK4, SHH, EDA and EDAR [23–28]. In mice HF, MYC expression is predominantly expressed in the epithelium and is related to the differentiation and proliferation of keratinocytes and stem cells migration during HF morphogenesis [29]. SP5, in its turn, is a direct target of β-catenin capable of inhibiting expression of KRT10 and IVL. Both products of these genes are associated with epidermal differentiation fate and, as a consequence, they may be suppressed to promote placode formation [30]. Dkk molecules are widely recognized for its inhibitory effects against Lrp5 and 6, which are crucial co-receptors in the activation of Wnt pathway [31]. Strong evidences have shown that DKK4 expression is a Wnt target gene in epidermis, an evidence that Dkk4 acts as Wnt pathway negative feedback loop, fine-tuning this signaling effects on placode shape [25].
SHH expression starts in the induction stage and is also upregulated by Wnt pathway in HF epithelium [32]. After secretion, Shh signal activates Shh signaling pathway in the mesenchyme compartment activating transcription factors Gli, which induces expression of Shh receptor Ptch, increasing cell sensibility to Shh [26,33].
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