BMP-FGF Signaling Axis Mediates Wnt-Induced Epidermal Stratification in Developing Mammalian Skin

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Epidermis, a thin layer of stratified epithelium forming the outmost surface of the skin, provides the crucial function to protect animals from environmental insults, such as bacterial pathogens and water loss. This barrier function is established in embryogenesis, during which single layered epithelial cells differentiate into distinct layers of keratinocytes. Many human genetic diseases are featured with epidermal disruption, affecting at least one in five patients. Skin regeneration and future therapeutics require a thorough understanding of the molecular mechanisms underlying epidermal stratification. Wnt ligands have been implicated in hair follicle induction during skin development and self-renewal of stem cells in the interfollicular epidermis of adult skin; however, little is known about the mechanism of how Wnt signaling controls epidermal stratification during embryogenesis. In this study, by using a genetic mouse model to disrupt Wnt production in skin development, we found that signaling of epidermal Wnt in the dermis initiate mesenchymal responses by activating a Bone Morphogenetic Protein (BMP) and Fibroblast growth factor (FGF) signaling cascade, and this activation is required for feedback regulations in the embryonic epidermis to control stratification. Our findings identify a genetic hierarchy of signaling essential for epidermal-mesenchymal interactions, and promote our understanding of mammalian skin development.

Vyšlo v časopise: BMP-FGF Signaling Axis Mediates Wnt-Induced Epidermal Stratification in Developing Mammalian Skin. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004687
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004687

Souhrn

Zdroje

1. FuchsE (2007) Scratching the surface of skin development. Nature 445: 834–842.

2. KosterMI, RoopDR (2007) Mechanisms regulating epithelial stratification. Annu Rev Cell Dev Biol 23: 93–113.

3. LechlerT, FuchsE (2005) Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437: 275–280.

4. KosterMI, KimS, MillsAA, DeMayoFJ, RoopDR (2004) p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 18: 126–131.

5. KosterMI, DaiD, MarinariB, SanoY, CostanzoA, et al. (2007) p63 induces key target genes required for epidermal morphogenesis. Proc Natl Acad Sci U S A 104: 3255–3260.

6. MillsAA, ZhengB, WangXJ, VogelH, RoopDR, et al. (1999) p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398: 708–713.

7. YangA, SchweitzerR, SunD, KaghadM, WalkerN, et al. (1999) p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398: 714–718.

8. YangA, KaghadM, WangY, GillettE, FlemingMD, et al. (1998) p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2: 305–316.

9. LeBoeufM, TerrellA, TrivediS, SinhaS, EpsteinJA, et al. (2010) Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells. Dev Cell 19: 807–818.

10. SenooM, PintoF, CrumCP, McKeonF (2007) p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129: 523–536.

11. AndlT, ReddyST, GaddaparaT, MillarSE (2002) WNT signals are required for the initiation of hair follicle development. Dev Cell 2: 643–653.

12. ReddyS, AndlT, BagasraA, LuMM, EpsteinDJ, et al. (2001) 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 107: 69–82.

13. SuzukiK, YamaguchiY, VillacorteM, MiharaK, AkiyamaM, et al. (2009) Embryonic hair follicle fate change by augmented beta-catenin through Shh and Bmp signaling. Development 136: 367–372.

14. FuJ, HsuW (2013) Epidermal Wnt controls hair follicle induction by orchestrating dynamic signaling crosstalk between the epidermis and dermis. J Invest Dermatol 133: 890–898.

15. ZhangY, AndlT, YangSH, TetaM, LiuF, et al. (2008) Activation of beta-catenin signaling programs embryonic epidermis to hair follicle fate. Development 135: 2161–2172.

16. SternCD (2005) Neural induction: old problem, new findings, yet more questions. Development 132: 2007–2021.

17. WilsonSI, EdlundT (2001) Neural induction: toward a unifying mechanism. Nat Neurosci 4 Suppl: 1161–1168.

18. LaurikkalaJ, MikkolaML, JamesM, TummersM, MillsAA, et al. (2006) p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation. Development 133: 1553–1563.

19. MedawarA, VirolleT, RostagnoP, de la Forest-DivonneS, GambaroK, et al. (2008) DeltaNp63 is essential for epidermal commitment of embryonic stem cells. PLoS One 3: e3441.

20. KobielakK, PasolliHA, AlonsoL, PolakL, FuchsE (2003) Defining BMP functions in the hair follicle by conditional ablation of BMP receptor IA. J Cell Biol 163: 609–623.

21. MouC, JacksonB, SchneiderP, OverbeekPA, HeadonDJ (2006) Generation of the primary hair follicle pattern. Proc Natl Acad Sci U S A 103: 9075–9080.

22. KawanoM, Komi-KuramochiA, AsadaM, SuzukiM, OkiJ, et al. (2005) Comprehensive analysis of FGF and FGFR expression in skin: FGF18 is highly expressed in hair follicles and capable of inducing anagen from telogen stage hair follicles. J Invest Dermatol 124: 877–885.

23. PetiotA, ContiFJ, GroseR, RevestJM, Hodivala-DilkeKM, et al. (2003) A crucial role for Fgfr2-IIIb signalling in epidermal development and hair follicle patterning. Development 130: 5493–5501.

24. RichardsonGD, BazziH, FantauzzoKA, WatersJM, CrawfordH, et al. (2009) KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin. Development 136: 2153–2164.

25. TaoH, YoshimotoY, YoshiokaH, NohnoT, NojiS, et al. (2002) FGF10 is a mesenchymally derived stimulator for epidermal development in the chick embryonic skin. Mech Dev 116: 39–49.

26. OhuchiH, HoriY, YamasakiM, HaradaH, SekineK, et al. (2000) FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem Biophys Res Commun 277: 643–649.

27. GuoL, DegensteinL, FuchsE (1996) Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev 10: 165–175.

28. GuoL, YuQC, FuchsE (1993) Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice. EMBO J 12: 973–986.

29. BanzigerC, SoldiniD, SchuttC, ZipperlenP, HausmannG, et al. (2006) Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 125: 509–522.

30. FuJ, Ivy YuHM, MaruyamaT, MirandoAJ, HsuW (2011) Gpr177/mouse Wntless is essential for Wnt-mediated craniofacial and brain development. Dev Dyn 240: 365–371.

31. FuJ, JiangM, MirandoAJ, YuHM, HsuW (2009) Reciprocal regulation of Wnt and Gpr177/mouse Wntless is required for embryonic axis formation. Proc Natl Acad Sci U S A 106: 18598–18603.

32. ZhuX, ZhaoP, LiuY, ZhangX, FuJ, et al. (2013) Intra-epithelial requirement of canonical Wnt signaling for tooth morphogenesis. J Biol Chem 288: 12080–12089.

33. ChenD, JarrellA, GuoC, LangR, AtitR (2012) Dermal beta-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation. Development 139: 1522–1533.

34. HeF, XiongW, WangY, MatsuiM, YuX, et al. (2010) Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis. Dev Biol 347: 109–121.

35. HeF, HuX, XiongW, LiL, LinL, et al. (2014) Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect. Dev Biol 391: 170–81 doi: 10.1016/j.ydbio.2014.04.013

36. AndlT, AhnK, KairoA, ChuEY, Wine-LeeL, et al. (2004) Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development. Development 131: 2257–2268.

37. SoshnikovaN, ZechnerD, HuelskenJ, MishinaY, BehringerRR, et al. (2003) Genetic interaction between Wnt/beta-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb. Genes Dev 17: 1963–1968.

38. RomanoRA, SmalleyK, MagrawC, SernaVA, KuritaT, et al. (2012) DeltaNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. Development 139: 772–782.

39. BeerHD, GassmannMG, MunzB, SteilingH, EngelhardtF, et al. (2000) Expression and function of keratinocyte growth factor and activin in skin morphogenesis and cutaneous wound repair. J Investig Dermatol Symp Proc 5: 34–39.

40. ZhangX, IbrahimiOA, OlsenSK, UmemoriH, MohammadiM, et al. (2006) Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281: 15694–15700.

41. MorikawaM, KoinumaD, TsutsumiS, VasilakiE, KankiY, et al. (2011) ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif. Nucleic Acids Res 39: 8712–8727.

42. MorikawaM, KoinumaD, MiyazonoK, HeldinCH (2013) Genome-wide mechanisms of Smad binding. Oncogene 32: 1609–1615.

43. NguyenH, MerrillBJ, PolakL, NikolovaM, RendlM, et al. (2009) Tcf3 and Tcf4 are essential for long-term homeostasis of skin epithelia. Nat Genet 41: 1068–1075.

44. RendlM, PolakL, FuchsE (2008) BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev 22: 543–557.

45. TruongAB, KretzM, RidkyTW, KimmelR, KhavariPA (2006) p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev 20: 3185–3197.

46. RomanoRA, OrttK, BirkayaB, SmalleyK, SinhaS (2009) An active role of the DeltaN isoform of p63 in regulating basal keratin genes K5 and K14 and directing epidermal cell fate. PLoS One 4: e5623.

47. TadeuAM, HorsleyV (2013) Notch signaling represses p63 expression in the developing surface ectoderm. Development 140: 3777–3786.

48. LimX, TanSH, KohWL, ChauRM, YanKS, et al. (2013) Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342: 1226–1230.

49. KandybaE, LeungY, ChenYB, WidelitzR, ChuongCM, et al. (2013) Competitive balance of intrabulge BMP/Wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation. Proc Natl Acad Sci U S A 110: 1351–1356.

50. PanchisionDM, PickelJM, StuderL, LeeSH, TurnerPA, et al. (2001) Sequential actions of BMP receptors control neural precursor cell production and fate. Genes Dev 15: 2094–2110.

51. DickA, RisauW, DrexlerH (1998) Expression of Smad1 and Smad2 during embryogenesis suggests a role in organ development. Dev Dyn 211: 293–305.

52. FessingMY, AtoyanR, ShanderB, MardaryevAN, BotchkarevVVJr, et al. (2010) BMP signaling induces cell-type-specific changes in gene expression programs of human keratinocytes and fibroblasts. J Invest Dermatol 130: 398–404.

53. FlandersKC, KimES, RobertsAB (2001) Immunohistochemical expression of Smads 1–6 in the 15-day gestation mouse embryo: signaling by BMPs and TGF-betas. Dev Dyn 220: 141–154.

54. BlessingM, SchirmacherP, KaiserS (1996) Overexpression of bone morphogenetic protein-6 (BMP-6) in the epidermis of transgenic mice: inhibition or stimulation of proliferation depending on the pattern of transgene expression and formation of psoriatic lesions. J Cell Biol 135: 227–239.

55. HaradaH, ToyonoT, ToyoshimaK, OhuchiH (2002) FGF10 maintains stem cell population during mouse incisor development. Connect Tissue Res 43: 201–204.

56. CandiE, RufiniA, TerrinoniA, Giamboi-MiragliaA, LenaAM, et al. (2007) DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2. Proc Natl Acad Sci U S A 104: 11999–12004.

57. OgawaE, OkuyamaR, EgawaT, NagoshiH, ObinataM, et al. (2008) p63/p51-induced onset of keratinocyte differentiation via the c-Jun N-terminal kinase pathway is counteracted by keratinocyte growth factor. J Biol Chem 283: 34241–34249.

58. FeroneG, ThomasonHA, AntoniniD, De RosaL, HuB, et al. (2012) Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome. EMBO Mol Med 4: 192–205.

59. LanderAD, GokoffskiKK, WanFY, NieQ, CalofAL (2009) Cell lineages and the logic of proliferative control. PLoS Biol 7: e15.

60. ChoiYS, ZhangY, XuM, YangY, ItoM, et al. (2013) Distinct functions for Wnt/beta-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell 13: 720–733.

61. DassuleHR, LewisP, BeiM, MaasR, McMahonAP (2000) Sonic hedgehog regulates growth and morphogenesis of the tooth. Development 127: 4775–4785.

62. DasGuptaR, FuchsE (1999) Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126: 4557–4568.

63. MarettoS, CordenonsiM, DupontS, BraghettaP, BroccoliV, et al. (2003) Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci U S A 100: 3299–3304.