Hair follicle development: induction - Part 1 of 3 (Homo sapiens)

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FGF20ct: codingDermal MesenchymeEpidermisTCF\\\\DegradationOR\\PlacodeFormationBMPactiveFGFR2IKBKGTP63WNT10BKRT10ct: codingSP5EDAMYCct: codingKRT10CTGFNFKBIBct: codingBMPR1AATPBMP4EGFRLEF1FOXI3ct: codingct: codingFSTct: codingWNT10WNT10ct: codingVCANIKBKBDVLIKKinactiveWNT10AN:3?NOGGINIVLct: codingINHBACHUKEDARct: codingSP5ct: codingEDAct: codingSHHct: codingDKK4ct: codingTCFLEF1Catenin-beta1IVLTCF3TCF4TCFLEF1Catenin-beta1NFKB1EDAREDAREDANFKBIBPNFKB1IKK (Complex)IKKN:3activeADPNFKB1SP5WNT10CellProliferationPlacodeShapeBMPR1ABMPBMPactiveNCAM1ct: codingMSX2ct: codingPlacodeFormationLEF1LRPLRP5LRPLRP6NOGGINBMPinactiveFOLLISTATINCTGFFRIZZLEDFRIZZLEDFZD1?WNT (1st)LRPFRIZZLEDWNT (1st)WNT (1st)NOGct: codingFOLLISTATINCTGF?LRPFRIZZLEDLRPFRIZZLEDWNT10FGF20FGF20FGFR1FGF20FGFR1RASinactiveRASactive\\DVLDVL1DVL2DVL3GSK3BATPADPCatenin-beta1activeCatenin-beta1Pinactive\\Catenin-beta1inactivePUbTCFLEF1Catenin-beta1TCFLEF1Catenin-beta1CTNNB1ct: codingVCANct: codingDermalAggregativeGrowthDermalAggregativeGrowthDegradationDVLGSK3BATPADPCatenin-beta1activeCatenin-beta1inactiveP\\Catenin-beta1PinactiveUbSHHDKK4PTCH1activePTCH1inactiveSHHSMOinactiveGLIPTCH1ct: codingGLIGLI1GLI2SMOactiveINHBATP63ct: codingFGFR2ct: codingEGFRct: codingGJB6ct: codingCDH3ct: codingCDH3GJB6EGFFGF7PlacodeFormationPlacodeShapeTP63


The hair follicle (HF) is the biological unit responsible for producing a single hair shaft. The follicles are arranged with concentric epithelial progenitor layers surrounding the dermal core, which is the dermal papilla (DP). Classically, the development of the follicle itself can be divided into three stages: Induction, Organogenesis and Cytodifferentiation.

In HF development, the induction stage marks the beginning of the crosstalk between epithelium and mesenchyme. Epithelium will result in the placode, which will give origin to most of the layers of the HF. Then, mesenchyme results in the dermal condensate, which thereafter becomes the dermal papilla.

The first signal for induction is given by mesenchymal cells expressing WNT. Activation of Wnt signalling pathway blocks β-catenin degradation fate, releasing this transcription factor to start expression of placode formation genes. Between them are MYC, SP5, DKK4, SHH, EDA and EDAR.

MYC is related to the differentiation and proliferation of keratinocytes and stem cells migration. SP5 is capable of inhibiting expression of KRT10 and IVL, both associated with epidermal differentiation fate. As a consequence, they may be suppressed to promote placode formation.

Dkk molecules have inhibitory effects against Lrp5 and 6, which are crucial co-receptors in the activation of Wnt pathway. Dkk4 acts as Wnt pathway negative feedback loop, fine-tuning this signalling effects on placode shape.

SHH expression starts in the induction stage and is also upregulated by Wnt pathway in HF epithelium. Its signal activates Shh signaling pathway in the mesenchyme activating Gli, which induces expression of Ptch, increasing cell sensibility to Shh. Wnt pathway is able to increase EDA expression, whereas Eda pathway does not affect Wnt signal levels. EDAR is a direct Wnt target, and Activin A acts as another upregulator. Furthermore, the Eda-Edar interaction activates NF-kappaB, which upregulates a considerable number of genes, including SHH, DKK4, WNT genes as WNT10A and WNT10B, FOXI3, FGF20, CTGF and FST. WNT10A and WNT10B 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.

Once the placode has started forming, Eda/NF-kappaB pathway has an important role in guiding cell proliferation. NF-kappaB and Activin A upregulates FOXI3, which has roles in skin appendages shape formation and possibly in placode shape patterning. Other genes also related to placode formation include CDH3 and GJB6, both induced by transcriptional activator TP63.

The Eda pathway induces FGF20 expression, which binds to Fgfr1, promoting the dermal condensate aggregative growth, also sustained by Versican (VCAN) expression mediated by mesenchymal Wnt pathway.

At induction, strong induction suppressor signals are present, such as Bmp, Fgf7 and Egf and they have to be inhibited. Molecules such as Noggin, Follistatin and CTGF act as BMP signal suppressors. Crucial placodal genes downregulated by BMP are LEF1 and NCAM, but BMP is also capable of inducing early upregulation of differentiation fate transcription factor Msx2.

Two other signals Fgf7 and Egf direct differentiation toward the epidermal fate, instead of inducing HF placode formation. These signals persist during induction stage, and their receptors (FGFR1 and EGFR, respectively) are downregulated in the placode to allow the correct HF development.

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118091view10:53, 24 May 2021EweitzModified title
115431view10:46, 19 February 2021DeSlAdded other 2 PWs in description with linkout
115430view10:35, 19 February 2021DeSlRemoved email address + last modified item
115429view10:34, 19 February 2021DeSlSmall title change
106725view13:19, 17 September 2019MkutmonHMDB identifier normalization
88629view14:39, 12 August 2016JmeliusOntology Term : 'regulatory pathway' added !
79882view12:11, 23 April 2015Mkutmonadded xrefs for ATP and ADP
79881view12:07, 23 April 2015Mkutmonchanged datanodes without text label to labels
78710view13:44, 18 January 2015EgonwManually added some missing graph IDs.
77319view00:35, 15 August 2014DanieltrinunesModified description
77318view00:34, 15 August 2014DanieltrinunesModified description
77317view22:37, 14 August 2014Danieltrinunes
77316view22:36, 14 August 2014Danieltrinunes
77314view22:27, 14 August 2014DanieltrinunesModified description
75844view21:26, 10 June 2014DanieltrinunesModified title
75843view21:14, 10 June 2014DanieltrinunesChanges in accordance to SBGN pattern.
75842view21:08, 10 June 2014Danieltrinunesok
75524view20:06, 6 June 2014Daniel.trinunesModified title
75437view15:52, 30 May 2014Daniel.trinunesModified description
75373view20:46, 20 May 2014Daniel.trinunesModified description
75372view20:43, 20 May 2014Daniel.trinunesModified description
75371view20:22, 20 May 2014Daniel.trinunesModified description
75370view20:19, 20 May 2014Daniel.trinunesModified description
75369view20:18, 20 May 2014Daniel.trinunesModified description
75228view19:27, 12 May 2014Daniel.trinunesNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetaboliteHMDB0001341 (HMDB)
ATPMetaboliteHMDB0000538 (HMDB)
BMP4GeneProductENSG00000125378 (Ensembl)
BMPR1AGeneProductENSG00000107779 (Ensembl)
CDH3GeneProductENSG00000062038 (Ensembl)
CHUKGeneProductENSG00000213341 (Ensembl)
CTGFGeneProductENSG00000118523 (Ensembl)
CTNNB1GeneProductENSG00000168036 (Ensembl)
Catenin-beta1GeneProductENSG00000168036 (Ensembl)
DKK4GeneProductENSG00000104371 (Ensembl)
DVL1GeneProductENSG00000107404 (Ensembl)
DVL2GeneProductENSG00000107404 (Ensembl)
DVL3GeneProductENSG00000107404 (Ensembl)
EDAGeneProductENSG00000158813 (Ensembl)
EDARGeneProductENSG00000135960 (Ensembl)
EGFGeneProductENSG00000138798 (Ensembl)
EGFRGeneProductENSG00000146648 (Ensembl)
FGF20GeneProductENSG00000078579 (Ensembl)
FGF7GeneProductENSG00000140285 (Ensembl)
FGFR1GeneProductENSG00000077782 (Ensembl)
FGFR2GeneProductENSG00000066468 (Ensembl)
FOLLISTATINGeneProductENSG00000134363 (Ensembl)
FOXI3GeneProductENSG00000214336 (Ensembl)
FSTGeneProductENSG00000134363 (Ensembl)
FZD1GeneProductENSG00000157240 (Ensembl)
GJB6GeneProductENSG00000121742 (Ensembl)
GLI1GeneProductENSG00000107404 (Ensembl)
GLI2GeneProductENSG00000107404 (Ensembl)
GSK3BGeneProductENSG00000082701 (Ensembl)
IKBKBGeneProductENSG00000104365 (Ensembl)
IKBKGGeneProductENSG00000073009 (Ensembl)
INHBAGeneProductENSG00000122641 (Ensembl)
IVLGeneProductENSG00000163207 (Ensembl)
KRT10GeneProductENSG00000186395 (Ensembl)
LEF1GeneProductENSG00000138795 (Ensembl)
LRP5GeneProductENSG00000162337 (Ensembl)
LRP6GeneProductENSG00000070018 (Ensembl)
MSX2GeneProductENSG00000120149 (Ensembl)
MYCGeneProductENSG00000136997 (Ensembl)
NCAM1GeneProductENSG00000262279 (Ensembl)
NFKB1GeneProductENSG00000109320 (Ensembl)
NFKBIBGeneProductENSG00000104825 (Ensembl)
NOGGeneProductENSG00000183691 (Ensembl)
NOGGINGeneProductENSG00000183691 (Ensembl)
PTCH1GeneProductENSG00000185920 (Ensembl)
SHHGeneProductENSG00000164690 (Ensembl)
SMOGeneProductENSG00000128602 (Ensembl)
SP5GeneProductENSG00000204335 (Ensembl)
TCF3GeneProductENSG00000071564 (Ensembl)
TCF4GeneProductENSG00000071564 (Ensembl)
TP63GeneProductENSG00000073282 (Ensembl)
VCANGeneProductENSG00000038427 (Ensembl)
WNT (1st)Protein
WNT10AGeneProductENSG00000135925 (Ensembl)
WNT10BGeneProductENSG00000169884 (Ensembl)
WNT10GeneProductENSG00000135925 (Ensembl)

Annotated Interactions

No annotated interactions

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