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)IKKactiveN:3ADPNFKB1SP5WNT10CellProliferationPlacodeShapeBMPR1ABMPBMPactiveNCAM1ct: codingMSX2ct: codingPlacodeFormationLEF1LRPLRP5LRPLRP6NOGGINBMPinactiveFOLLISTATINCTGFFRIZZLEDFRIZZLEDFZD1?WNT (1st)LRPFRIZZLEDWNT (1st)WNT (1st)NOGct: codingFOLLISTATINCTGF?LRPFRIZZLEDLRPFRIZZLEDWNT10FGF20FGF20FGFR1FGF20FGFR1RASinactiveRASactive\\DVLDVL1DVL2DVL3GSK3BATPADPCatenin-beta1activeCatenin-beta1Pinactive\\Catenin-beta1UbinactivePTCFLEF1Catenin-beta1TCFLEF1Catenin-beta1CTNNB1ct: codingVCANct: codingDermalAggregativeGrowthDermalAggregativeGrowthDegradationDVLGSK3BATPADPCatenin-beta1activeCatenin-beta1inactiveP\\Catenin-beta1PUbinactiveSHHDKK4PTCH1activePTCH1inactiveSHHSMOinactiveGLIPTCH1ct: codingGLIGLI1GLI2SMOactiveINHBATP63ct: codingFGFR2ct: codingEGFRct: codingGJB6ct: codingCDH3ct: codingCDH3GJB6EGFFGF7PlacodeFormationPlacodeShapeTP63


Description

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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Bibliography

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  1. Richardson GD, Bazzi H, Fantauzzo KA, Waters JM, Crawford H, Hynd P, Christiano AM, Jahoda CA; ''KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin.''; Development, 2009 PubMed Europe PMC
  2. Bazzi H, Fantauzzo KA, Richardson GD, Jahoda CA, Christiano AM; ''The Wnt inhibitor, Dickkopf 4, is induced by canonical Wnt signaling during ectodermal appendage morphogenesis.''; Dev Biol, 2007 PubMed Europe PMC
  3. Cui CY, Kunisada M, Childress V, Michel M, Schlessinger D; ''Shh is required for Tabby hair follicle development.''; Cell Cycle, 2011 PubMed Europe PMC
  4. Chiang C, Swan RZ, Grachtchouk M, Bolinger M, Litingtung Y, Robertson EK, Cooper MK, Gaffield W, Westphal H, Beachy PA, Dlugosz AA; ''Essential role for Sonic hedgehog during hair follicle morphogenesis.''; Dev Biol, 1999 PubMed Europe PMC
  5. Schneider MR, Schmidt-Ullrich R, Paus R; ''The hair follicle as a dynamic miniorgan.''; Curr Biol, 2009 PubMed Europe PMC
  6. Mukhopadhyay M, Gorivodsky M, Shtrom S, Grinberg A, Niehrs C, Morasso MI, Westphal H; ''Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium.''; Development, 2006 PubMed Europe PMC
  7. Mou C, Jackson B, Schneider P, Overbeek PA, Headon DJ; ''Generation of the primary hair follicle pattern.''; Proc Natl Acad Sci U S A, 2006 PubMed Europe PMC
  8. Shimomura Y, Wajid M, Shapiro L, Christiano AM; ''P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle.''; Development, 2008 PubMed Europe PMC
  9. Yamaguchi TP, Bradley A, McMahon AP, Jones S; ''A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo.''; Development, 1999 PubMed Europe PMC
  10. Nowak JA, Polak L, Pasolli HA, Fuchs E; ''Hair follicle stem cells are specified and function in early skin morphogenesis.''; Cell Stem Cell, 2008 PubMed Europe PMC
  11. Zhang Y, Andl T, Yang SH, Teta M, Liu F, Seykora JT, Tobias JW, Piccolo S, Schmidt-Ullrich R, Nagy A, Taketo MM, Dlugosz AA, Millar SE; ''Activation of beta-catenin signaling programs embryonic epidermis to hair follicle fate.''; Development, 2008 PubMed Europe PMC
  12. Fliniaux I, Mikkola ML, Lefebvre S, Thesleff I; ''Identification of dkk4 as a target of Eda-A1/Edar pathway reveals an unexpected role of ectodysplasin as inhibitor of Wnt signalling in ectodermal placodes.''; Dev Biol, 2008 PubMed Europe PMC
  13. Fujimoto A, Kurban M, Nakamura M, Farooq M, Fujikawa H, Kibbi AG, Ito M, Dahdah M, Matta M, Diab H, Shimomura Y; ''GJB6, of which mutations underlie Clouston syndrome, is a potential direct target gene of p63.''; J Dermatol Sci, 2013 PubMed Europe PMC
  14. Niemann C, Unden AB, Lyle S, Zouboulis ChC, Toftgård R, Watt FM; ''Indian hedgehog and beta-catenin signaling: role in the sebaceous lineage of normal and neoplastic mammalian epidermis.''; Proc Natl Acad Sci U S A, 2003 PubMed Europe PMC
  15. Reddy S, Andl T, Bagasra A, Lu MM, Epstein DJ, Morrisey EE, Millar SE; ''Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis.''; Mech Dev, 2001 PubMed Europe PMC
  16. Hens JR, Dann P, Zhang JP, Harris S, Robinson GW, Wysolmerski J; ''BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction.''; Development, 2007 PubMed Europe PMC
  17. Yang Y, Li Y, Wang Y, Wu J, Yang G, Yang T, Gao Y, Lu Y; ''Versican gene: regulation by the β-catenin signaling pathway plays a significant role in dermal papilla cell aggregative growth.''; J Dermatol Sci, 2012 PubMed Europe PMC
  18. Rishikaysh P, Dev K, Diaz D, Qureshi WM, Filip S, Mokry J; ''Signaling involved in hair follicle morphogenesis and development.''; Int J Mol Sci, 2014 PubMed Europe PMC
  19. Tsai SY, Sennett R, Rezza A, Clavel C, Grisanti L, Zemla R, Najam S, Rendl M; ''Wnt/β-catenin signaling in dermal condensates is required for hair follicle formation.''; Dev Biol, 2014 PubMed Europe PMC
  20. Huh SH, Närhi K, Lindfors PH, Häärä O, Yang L, Ornitz DM, Mikkola ML; ''Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles.''; Genes Dev, 2013 PubMed Europe PMC
  21. Laurikkala J, Pispa J, Jung HS, Nieminen P, Mikkola M, Wang X, Saarialho-Kere U, Galceran J, Grosschedl R, Thesleff I; ''Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar.''; Development, 2002 PubMed Europe PMC
  22. Wang N, Yang T, Li J, Lei M, Shi J, Qiu W, Lian X; ''The expression and role of c-Myc in mouse hair follicle morphogenesis and cycling.''; Acta Histochem, 2012 PubMed Europe PMC
  23. da Silva-Diz V, Solé-Sánchez S, Valdés-Gutiérrez A, Urpí M, Riba-Artés D, Penin RM, Pascual G, González-Suárez E, Casanovas O, Viñals F, Paramio JM, Batlle E, Muñoz P; ''Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus-induced tumor development in epidermis.''; Oncogene, 2013 PubMed Europe PMC
  24. Mardaryev AN, Meier N, Poterlowicz K, Sharov AA, Sharova TY, Ahmed MI, Rapisarda V, Lewis C, Fessing MY, Ruenger TM, Bhawan J, Werner S, Paus R, Botchkarev VA; ''Lhx2 differentially regulates Sox9, Tcf4 and Lgr5 in hair follicle stem cells to promote epidermal regeneration after injury.''; Development, 2011 PubMed Europe PMC
  25. Zhang Y, Tomann P, Andl T, Gallant NM, Huelsken J, Jerchow B, Birchmeier W, Paus R, Piccolo S, Mikkola ML, Morrisey EE, Overbeek PA, Scheidereit C, Millar SE, Schmidt-Ullrich R; ''Reciprocal requirements for EDA/EDAR/NF-kappaB and Wnt/beta-catenin signaling pathways in hair follicle induction.''; Dev Cell, 2009 PubMed Europe PMC
  26. Pummila M, Fliniaux I, Jaatinen R, James MJ, Laurikkala J, Schneider P, Thesleff I, Mikkola ML; ''Ectodysplasin has a dual role in ectodermal organogenesis: inhibition of Bmp activity and induction of Shh expression.''; Development, 2007 PubMed Europe PMC
  27. Ridgway RA, Serrels B, Mason S, Kinnaird A, Muir M, Patel H, Muller WJ, Sansom OJ, Brunton VG; ''Focal adhesion kinase is required for β-catenin-induced mobilization of epidermal stem cells.''; Carcinogenesis, 2012 PubMed Europe PMC
  28. Shirokova V, Jussila M, Hytönen MK, Perälä N, Drögemüller C, Leeb T, Lohi H, Sainio K, Thesleff I, Mikkola ML; ''Expression of Foxi3 is regulated by ectodysplasin in skin appendage placodes.''; Dev Dyn, 2013 PubMed Europe PMC
  29. Botchkarev VA, Botchkareva NV, Roth W, Nakamura M, Chen LH, Herzog W, Lindner G, McMahon JA, Peters C, Lauster R, McMahon AP, Paus R; ''Noggin is a mesenchymally derived stimulator of hair-follicle induction.''; Nat Cell Biol, 1999 PubMed Europe PMC
  30. Durmowicz MC, Cui CY, Schlessinger D; ''The EDA gene is a target of, but does not regulate Wnt signaling.''; Gene, 2002 PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
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

DataNodes

View all...
NameTypeDatabase referenceComment
?
ADPMetaboliteHMDB0001341 (HMDB)
ATPMetaboliteHMDB0000538 (HMDB)
BMPProtein
BMP4GeneProductENSG00000125378 (Ensembl)
BMPR1AGeneProductENSG00000107779 (Ensembl)
CDH3GeneProductENSG00000062038 (Ensembl)
CHUKGeneProductENSG00000213341 (Ensembl)
CTGFGeneProductENSG00000118523 (Ensembl)
CTNNB1GeneProductENSG00000168036 (Ensembl)
Catenin-beta1GeneProductENSG00000168036 (Ensembl)
DKK4GeneProductENSG00000104371 (Ensembl)
DVLProtein
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)
FRIZZLEDProtein
FSTGeneProductENSG00000134363 (Ensembl)
FZD1GeneProductENSG00000157240 (Ensembl)
GJB6GeneProductENSG00000121742 (Ensembl)
GLIProtein
GLI1GeneProductENSG00000107404 (Ensembl)
GLI2GeneProductENSG00000107404 (Ensembl)
GSK3BGeneProductENSG00000082701 (Ensembl)
IKBKBGeneProductENSG00000104365 (Ensembl)
IKBKGGeneProductENSG00000073009 (Ensembl)
IKKComplex
INHBAGeneProductENSG00000122641 (Ensembl)
IVLGeneProductENSG00000163207 (Ensembl)
KRT10GeneProductENSG00000186395 (Ensembl)
LEF1GeneProductENSG00000138795 (Ensembl)
LRPProtein
LRP5GeneProductENSG00000162337 (Ensembl)
LRP6GeneProductENSG00000070018 (Ensembl)
MSX2GeneProductENSG00000120149 (Ensembl)
MYCGeneProductENSG00000136997 (Ensembl)
NCAM1GeneProductENSG00000262279 (Ensembl)
NFKB1GeneProductENSG00000109320 (Ensembl)
NFKBIBGeneProductENSG00000104825 (Ensembl)
NOGGeneProductENSG00000183691 (Ensembl)
NOGGINGeneProductENSG00000183691 (Ensembl)
PTCH1GeneProductENSG00000185920 (Ensembl)
RASProtein
SHHGeneProductENSG00000164690 (Ensembl)
SMOGeneProductENSG00000128602 (Ensembl)
SP5GeneProductENSG00000204335 (Ensembl)
TCFProtein
TCF3GeneProductENSG00000071564 (Ensembl)
TCF4GeneProductENSG00000071564 (Ensembl)
TP63GeneProductENSG00000073282 (Ensembl)
VCANGeneProductENSG00000038427 (Ensembl)
WNT (1st)Protein
WNT10Protein
WNT10AGeneProductENSG00000135925 (Ensembl)
WNT10BGeneProductENSG00000169884 (Ensembl)
WNT10GeneProductENSG00000135925 (Ensembl)

Annotated Interactions

No annotated interactions

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