Hair follicle development: induction - stage 1 of 3 (Homo sapiens)
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Description
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 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. The first signal for induction is given by mesenchymal cells expressing WNT early in development. Although it is not known what specific Wnt is responsible for this first signal, some authors consider Wnt10b as a reasonable candidate. 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, 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.
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. 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.
Dkk molecules are widely recognized for its inhibitory effects against Lrp5 and 6, which are crucial co-receptors in the activation of Wnt pathway. 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.
SHH expression starts in the induction stage and is also upregulated by Wnt pathway in HF epithelium. 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.
Until this point in HF development, Wnt and Shh pathways are strongly operating between epithelium and mesenchymal compartments. Following MYC activation, epithelial cells proliferate and thus the placode begins to get its form. Co-transfection studies have shown that the Wnt pathway is able to increase EDA expression, whereas Eda pathway does not affect Wnt signal levels. As Figure 1A shows in the Epidermal compartment, Eda receptor’s gene EDAR is a direct Wnt target, and Activin A acts as another upregulator. Furthermore, the Eda-Edar interaction activates the transcription factor NF-kappaB, which upregulates a considerable number of genes, including SHH, DKK4, WNT genes as WNT10A and WNT10B, FOXI3, FGF20, CTGF and FST.
Similarly to Wnt, the Eda/NF-kappaB pathway upregulates SHH and DKK4. Eda also activates expression of Wnt genes such as WNT10A and WNT10B in the epithelial cells, which are indirectly and directly stimulated by NF-kappaB, respectively. Those two Wnt proteins activate the Wnt pathway in the mesenchymal cells, where released β-catenin activates expression of other Wnts and further upregulates its own expression, maintaining the tissue crosstalk and enhancing the signaling pathway performance. It is also known that mesenchymal β-catenin activity is important for epithelial β-catenin maintenance.
Placode and dermal condensate formation
Once the initial crosstalk is established and the placode has started forming, the tissues require instructions that guide cell proliferation. Once again the Eda/NF-kappaB pathway has an important role. NF-kappaB is responsible for upregulating FOXI3, a forkhead box family member expressed in teeth and HF during embryogenesis. It has roles in skin appendages shape formation and possibly in placode shape patterning. Furthermore, Activin A is also capable of upregulating Foxi3 in the epidermis.
Other genes also related to placode formation include gap junction protein genes CDH3 and GJB6, both induced by transcriptional activator TP63. After its establishment, the placode emits epidermal signals to the underneath mesenchymal cells, in a way to start their aggregation. The Eda pathway induces FGF20 expression in the epithelium that when secreted binds to its mesenchymal receptor Fgfr1, promoting the dermal condensate aggregative growth. Moreover, this aggregation is also sustained by Versican (VCAN) expression mediated by mesenchymal Wnt pathway.
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