The Mammary Bud as a Skin Appendage: Unique and Shared Aspects of Development

Article

Abstract

Like other skin appendages, the embryonic mammary gland develops via extensive epithelial–mesenchymal interactions. Early stages in embryonic mammary development strikingly resemble analogous steps in the development of hair follicles and teeth. In each case the first morphological sign of development is a localized thickening in the surface epithelium that subsequently invaginates to form a mammary, hair follicle or tooth bud. Similar sets of intersecting signaling pathways are involved in patterning the mammary, hair follicle and dental epithelium, directing placode formation, and controlling bud invagination. Despite these similarities, subsequent events in the formation of these appendages are diverse. The mammary bud extends to form a sprout that begins to branch upon contact with the mammary fat pad. Hair follicles also extend into the underlying mesenchyme, but instead of branching, hair follicle epithelium folds around a condensation of dermal cells. In contrast, teeth undergo a more complex folding morphogenesis. Here, we review what is known of the molecular and cellular mechanisms controlling early steps in the development of these organs, attempt to unravel both common themes and unique aspects that can begin to explain the diversity of appendage formation, and discuss human genetic diseases that affect appendage morphogenesis.

Keywords

Mammary placode Mammary bud Appendage Hair follicle Tooth Ectodermal Epidermis Embryo 

Abbreviations

ADULT

acro-dermato-ungual-lacrimal-tooth syndrome

APC

adenomatous Polyposis Coli

AREG

Amphiregulin

AEC

ankyloblepharon-ectodermal dysplasia-clefting syndrome

BCC

basal cell carcinoma

BMP

bone morphogenetic protein

DKK1

Dickkopf 1

EDA

Ectodysplasin

EDAR

edctodysplasin receptor

EEC

ectrodactyly-ectodermal-dysplasia-clefting syndrome

E

embryonic day

FGFR

fibroblast growth factor receptor

LMS

limb-mammary syndrome

NRG3

Neuregulin 3

SHFM

non-syndromic split-hand/split-foot malformation

PTHrP

parathyroid hormone-related protein

SEM

scanning electron microscopy

SHH

Sonic hedgehog

References

  1. 1.
    Sakakura T. Mammary embryogenesis. In: Neville MC, Daniel CW, editors. The mammary gland, development, regulation and function. New York and London: Plenum; 1987. p. 37–66.Google Scholar
  2. 2.
    Veltmaat JM, Mailleux AA, Thiery JP, Bellusci S. Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation. Differentiation 2003;71(1):1–17.PubMedGoogle Scholar
  3. 3.
    Veltmaat JM, Van Veelen W, Thiery JP, Bellusci S. Identification of the mammary line in mouse by Wnt10b expression. Dev Dyn 2004;229(2):349–56.PubMedGoogle Scholar
  4. 4.
    Propper AY. Wandering epithelial cells in the rabbit embryo milk line. A preliminary scanning electron microscope study. Dev Biol 1978;67(1):225–31.PubMedGoogle Scholar
  5. 5.
    Balinsky BI. On the pre-natal growth of the mammary gland rudiment in the mouse. J Anat 1950;84:227–35.PubMedGoogle Scholar
  6. 6.
    Sakakura T, Sakagami Y, Nishizuka Y. Dual origin of mesenchymal tissues participating in mouse mammary gland embryogenesis. Dev Biol 1982;91(1):202–7.PubMedGoogle Scholar
  7. 7.
    Chu EY, Hens J, Andl T, Kairo A, Yamaguchi TP, Brisken C, et al. Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 2004;131(19):4819–29.PubMedGoogle Scholar
  8. 8.
    DasGupta R, Fuchs E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 1999;126(20):4557–68.PubMedGoogle Scholar
  9. 9.
    Mailleux AA, Spencer-Dene B, Dillon C, Ndiaye D, Savona-Baron C, Itoh N, et al. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 2002;129(1):53–60.PubMedGoogle Scholar
  10. 10.
    Veltmaat JM, Relaix F, Le LT, Kratochwil K, Sala FG, van Veelen W, et al. Gli3-mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes. Development 2006;133(12):2325–35.PubMedGoogle Scholar
  11. 11.
    Howard B, Panchal H, McCarthy A, Ashworth A. Identification of the scaramanga gene implicates Neuregulin3 in mammary gland specification. Genes Dev 2005;19(17):2078–90.PubMedGoogle Scholar
  12. 12.
    Maretto S, Cordenonsi M, Dupont S, Braghetta P, Broccoli V, Hassan AB, et al. Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci USA 2003;100(6):3299–304.PubMedGoogle Scholar
  13. 13.
    Hens JR, Wysolmerski JJ. Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland. Breast Cancer Res 2005;7(5):220–4.PubMedGoogle Scholar
  14. 14.
    Eblaghie MC, Song SJ, Kim JY, Akita K, Tickle C, Jung HS. Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos. J Anat 2004;205(1):1–13.PubMedGoogle Scholar
  15. 15.
    Davenport TG, Jerome-Majewska LA, Papaioannou VE. Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 2003;130(10):2263–73.PubMedGoogle Scholar
  16. 16.
    Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 2004;18(2):126–31.PubMedGoogle Scholar
  17. 17.
    Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999;398(6729):708–13.PubMedGoogle Scholar
  18. 18.
    Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999;398(6729):714–8.PubMedGoogle Scholar
  19. 19.
    Fomenkov A, Huang YP, Topaloglu O, Brechman A, Osada M, Fomenkova T, et al. P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay–Wells syndrome. J Biol Chem 2003;278(26):23906–14.PubMedGoogle Scholar
  20. 20.
    Foley J, Dann P, Hong J, Cosgrove J, Dreyer B, Rimm D, et al. Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development. Development 2001;128(4):513–25.PubMedGoogle Scholar
  21. 21.
    Wysolmerski JJ, Philbrick WM, Dunbar ME, Lanske B, Kronenberg H, Broadus AE. Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development. Development 1998;125(7):1285–94.PubMedGoogle Scholar
  22. 22.
    Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet 2000;24(4):391–5.PubMedGoogle Scholar
  23. 23.
    Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z. Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin. Development 2005;132(17):3923–33.PubMedGoogle Scholar
  24. 24.
    Chakravarty G, Hadsell D, Buitrago W, Settleman J, Rosen JM. p190-B RhoGAP regulates mammary ductal morphogenesis. Mol Endocrinol 2003;17(6):1054–65.PubMedGoogle Scholar
  25. 25.
    Hardy MH. The secret life of the hair follicle. Trends Genet 1992;8(2):55–60.PubMedGoogle Scholar
  26. 26.
    Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol 2002;118(2):216–25.PubMedGoogle Scholar
  27. 27.
    Schmidt-Ullrich R, Paus R. Molecular principles of hair follicle induction and morphogenesis. BioEssays 2005;27(3):247–61.PubMedGoogle Scholar
  28. 28.
    Sperling LC. Hair anatomy for the clinician. J Am Acad Dermatol 1991;25(1 Pt 1):1–17.PubMedGoogle Scholar
  29. 29.
    Oliver RF, Jahoda CA. Dermal–epidermal interactions. Clin Dermatol 1988;6(4):74–82.PubMedGoogle Scholar
  30. 30.
    Jiang TX, Chuong CM. Mechanism of skin morphogenesis. I. Analyses with antibodies to adhesion molecules tenascin, N-CAM, and integrin. Dev Biol 1992;150(1):82–98.PubMedGoogle Scholar
  31. 31.
    Mandler M, Neubuser A. FGF signaling is required for initiation of feather placode development. Development 2004;131(14):3333–43.PubMedGoogle Scholar
  32. 32.
    Petiot A, Conti FJ, Grose R, Revest JM, Hodivala-Dilke KM, Dickson C. A crucial role for Fgfr2-IIIb signalling in epidermal development and hair follicle patterning. Development 2003;130(22):5493–501.PubMedGoogle Scholar
  33. 33.
    Laurikkala J, Pispa J, Jung HS, Nieminen P, Mikkola M, Wang X, et al. Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar. Development 2002;129(10):2541–53.PubMedGoogle Scholar
  34. 34.
    Noramly S, Freeman A, Morgan BA. beta-catenin signaling can initiate feather bud development. Development 1999;126(16):3509–21.PubMedGoogle Scholar
  35. 35.
    Kratochwil K, Dull M, Farinas I, Galceran J, Grosschedl R. Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development. Genes Dev 1996;10(11):1382–94.PubMedGoogle Scholar
  36. 36.
    Slack J. From egg to embryo. Cambridge, UK: Cambridge University Press; 1991.Google Scholar
  37. 37.
    Barsh G. Of ancient tales and hairless tails. Nat Genet 1999;22(4):315–6.PubMedGoogle Scholar
  38. 38.
    Gat U, DasGupta R, Degenstein L, Fuchs E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 1998;95(5):605–14.PubMedGoogle Scholar
  39. 39.
    Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. Beta-catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 2001;105:533–45.PubMedGoogle Scholar
  40. 40.
    van Genderen C, Okamura RM, Farinas I, Quo RG, Parslow TG, Bruhn L, et al. Development of several organs that require inductive epithelial–mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev 1994;8(22):2691–703.PubMedGoogle Scholar
  41. 41.
    Laurikkala J, Mikkola M, James M, Tummers M, Mills AA, Thesleff I. p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation. Development 2006;133(8):1553–63.PubMedGoogle Scholar
  42. 42.
    Schmidt-Ullrich R, Tobin DJ, Lenhard D, Schneider P, Paus R, Scheidereit C. NF-kappaB transmits Eda A1/EdaR signaling to activate Shh and cyclin D1 expression, and controls post-initiation hair placode down-growth. Development 2006;133(6):1045–57.PubMedGoogle Scholar
  43. 43.
    Mustonen T, Ilmonen M, Pummila M, Kangas AT, Laurikkala J, Jaatinen R, et al. Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages. Development 2004;131(20):4907–19.PubMedGoogle Scholar
  44. 44.
    Schmidt-Ullrich R, Aebischer T, Hulsken J, Birchmeier W, Klemm U, Scheidereit C. Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. Development 2001;128(19):3843–53.PubMedGoogle Scholar
  45. 45.
    Noveen A, Jiang TX, Ting-Berreth SA, Chuong CM. Homeobox genes Msx-1 and Msx-2 are associated with induction and growth of skin appendages. J Invest Dermatol 1995;104(5):711–9.PubMedGoogle Scholar
  46. 46.
    Andl T, Reddy ST, Gaddapara T, Millar SE. WNT signals are required for the initiation of hair follicle development. Dev Cell 2002;2(5):643–53.PubMedGoogle Scholar
  47. 47.
    Botchkarev VA, Botchkareva NV, Roth W, Nakamura M, Chen LH, Herzog W, et al. Noggin is a mesenchymally derived stimulator of hair-follicle induction. Nat Cell Biol 1999;1(3):158–64.PubMedGoogle Scholar
  48. 48.
    Noramly S, Morgan BA. BMPs mediate lateral inhibition at successive stages in feather tract development. Development 1998;125(19):3775–87.PubMedGoogle Scholar
  49. 49.
    Andl T, Ahn K, Kairo A, Chu EY, Wine-Lee L, Reddy ST, et al. Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development. Development 2004;131(10):2257–68.PubMedGoogle Scholar
  50. 50.
    St-Jacques B, Dassule HR, Karavanova I, Botchkarev VA, Li J, Danielian PS, et al. Sonic hedgehog signaling is essential for hair development. Curr Biol 1998;8(19):1058–68.PubMedGoogle Scholar
  51. 51.
    Chiang C, Swan RZ, Grachtchouk M, Bolinger M, Litingtung Y, Robertson EK, et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev Biol 1999;205(1):1–9.PubMedGoogle Scholar
  52. 52.
    Mill P, Mo R, Fu H, Grachtchouk M, Kim PC, Dlugosz AA, et al. Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development. Genes Dev 2003;17(2):282–94.PubMedGoogle Scholar
  53. 53.
    Mill P, Mo R, Hu MC, Dagnino L, Rosenblum ND, Hui CC. Shh controls epithelial proliferation via independent pathways that converge on N-Myc. Dev Cell 2005;9(2):293–303.PubMedGoogle Scholar
  54. 54.
    Headon DJ, Overbeek PA. Involvement of a novel Tnf receptor homologue in hair follicle induction. Nat Genet 1999;22(4):370–4.PubMedGoogle Scholar
  55. 55.
    Headon DJ, Emmal SA, Ferguson BM, Tucker AS, Justice MJ, Sharpe PT, et al. Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature 2001;414(6866):913–6.PubMedGoogle Scholar
  56. 56.
    Foitzik K, Paus R, Doetschman T, Dotto GP. The TGF-beta2 isoform is both a required and sufficient inducer of murine hair follicle morphogenesis. Dev Biol 1999;212(2):278–89.PubMedGoogle Scholar
  57. 57.
    Jamora C, Lee P, Kocieniewski P, Azhar M, Hosokawa R, Chai Y, et al. A signaling pathway involving TGF-beta2 and snail in hair follicle morphogenesis. PLoS Biol 2005;3(1):e11.PubMedGoogle Scholar
  58. 58.
    Jamora C, DasGupta R, Kocieniewski P, Fuchs E. Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 2003;422(6929):317–22.PubMedGoogle Scholar
  59. 59.
    Kobielak K, Pasolli HA, Alonso L, Polak L, Fuchs E. Defining BMP functions in the hair follicle by conditional ablation of BMP receptor IA. J Cell Biol 2003;163(3):609–23.PubMedGoogle Scholar
  60. 60.
    Yuhki M, Yamada M, Kawano M, Iwasato T, Itohara S, Yoshida H, et al. BMPR1A signaling is necessary for hair follicle cycling and hair shaft differentiation in mice. Development 2004;131(8):1825–33.PubMedGoogle Scholar
  61. 61.
    Ming Kwan K, Li AG, Wang XJ, Wurst W, Behringer RR. Essential roles of BMPR-IA signaling in differentiation and growth of hair follicles and in skin tumorigenesis. Genesis 2004;39(1):10–25.PubMedGoogle Scholar
  62. 62.
    Kaufman CK, Zhou P, Pasolli HA, Rendl M, Bolotin D, Lim KC, et al. GATA-3: an unexpected regulator of cell lineage determination in skin. Genes Dev 2003;17(17):2108–22.PubMedGoogle Scholar
  63. 63.
    Pan Y, Lin MH, Tian X, Cheng HT, Gridley T, Shen J, et al. Gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004;7(5):731–43.PubMedGoogle Scholar
  64. 64.
    Vidal VP, Chaboissier MC, Lutzkendorf S, Cotsarelis G, Mill P, Hui CC, et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr Biol 2005;15(15):1340–51.PubMedGoogle Scholar
  65. 65.
    Godwin AR, Capecchi MR. Hoxc13 mutant mice lack external hair. Genes Dev 1998;12(1):11–20.PubMedGoogle Scholar
  66. 66.
    Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 1994;372(6501):103–7.PubMedGoogle Scholar
  67. 67.
    Segre JA, Nemhauser JL, Taylor BA, Nadeau JH, Lander ES. Positional cloning of the nude locus: genetic, physical, and transcription maps of the region and mutations in the mouse and rat. Genomics 1995;28(3):549–59.PubMedGoogle Scholar
  68. 68.
    Brissette JL, Li J, Kamimura J, Lee D, Dotto GP. The product of the mouse nude locus, Whn, regulates the balance between epithelial cell growth and differentiation. Genes Dev 1996;10(17):2212–21.PubMedGoogle Scholar
  69. 69.
    Meier N, Dear TN, Boehm T. Whn and mHa3 are components of the genetic hierarchy controlling hair follicle differentiation. Mech Dev 1999;89(1–2):215–21.PubMedGoogle Scholar
  70. 70.
    Jernvall J, Thesleff I. Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 2000;92(1):19–29.PubMedGoogle Scholar
  71. 71.
    Cobourne MT, Sharpe PT. Tooth and jaw: molecular mechanisms of patterning in the first branchial arch. Arch Oral Biol 2003;48(1):1–14.PubMedGoogle Scholar
  72. 72.
    Wang X, Thesleff I. Tooth development. In: Unsicker K, Krieglstein K, editors. Cell signalling and growth factors in development. Weinhem: Wiley-VHC; 2006. p.719–754.Google Scholar
  73. 73.
    Peterkova R. The common developmental origin and phylogenetic aspects of teeth, rugae palatinae, and fornix vestibuli oris in the mouse. J Craniofac Genet Dev Biol 1985;5(1):89–104.PubMedGoogle Scholar
  74. 74.
    Mina M, Kollar EJ. The induction of odontogenesis in non-dental mesenchyme combined with early murine mandibular arch epithelium. Arch Oral Biol 1987;32(2):123–7.PubMedGoogle Scholar
  75. 75.
    Mucchielli ML, Mitsiadis TA, Raffo S, Brunet JF, Proust JP, Goridis C. Mouse Otlx2/RIEG expression in the odontogenic epithelium precedes tooth initiation and requires mesenchyme-derived signals for its maintenance. Dev Biol 1997;189(2):275–84.PubMedGoogle Scholar
  76. 76.
    Keranen SV, Kettunen P, Aberg T, Thesleff I, Jernvall J. Gene expression patterns associated with suppression of odontogenesis in mouse and vole diastema regions. Dev Genes Evol 1999;209(8):495–506.PubMedGoogle Scholar
  77. 77.
    Lu MF, Pressman C, Dyer R, Johnson RL, Martin JF. Function of Rieger syndrome gene in left–right asymmetry and craniofacial development. Nature 1999;401(6750):276–8.PubMedGoogle Scholar
  78. 78.
    Liu W, Selever J, Lu MF, Martin JF. Genetic dissection of Pitx2 in craniofacial development uncovers new functions in branchial arch morphogenesis, late aspects of tooth morphogenesis and cell migration. Development 2003;130(25):6375–85.PubMedGoogle Scholar
  79. 79.
    Sarkar L, Cobourne M, Naylor S, Smalley M, Dale T, Sharpe PT. Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proc Natl Acad Sci U S A 2000;97(9):4520–4.PubMedGoogle Scholar
  80. 80.
    Kassai Y, Munne P, Hotta Y, Penttila E, Kavanagh K, Ohbayashi N, et al. Regulation of mammalian tooth cusp patterning by ectodin. Science 2005;309(5743):2067–70.PubMedGoogle Scholar
  81. 81.
    Pispa J, Mikkola ML, Mustonen T, Thesleff I. Ectodysplasin, Edar and TNFRSF19 are expressed in complementary and overlapping patterns during mouse embryogenesis. Gene Expr Patterns 2003;3(5):675–9.PubMedGoogle Scholar
  82. 82.
    Thesleff I, Hurmerinta K. Tissue interactions in tooth development. Differentiation 1981;18(2):75–88.PubMedGoogle Scholar
  83. 83.
    Lumsden AG. Spatial organization of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ. Development 1988;103(Suppl):155–69.PubMedGoogle Scholar
  84. 84.
    Neubuser A, Peters H, Balling R, Martin GR. Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 1997;90(2):247–55.PubMedGoogle Scholar
  85. 85.
    Ferguson CA, Tucker AS, Heikinheimo K, Nomura M, Oh P, Li E, et al. The role of effectors of the activin signalling pathway, activin receptors IIA and IIB, and Smad2, in patterning of tooth development. Development 2001;128(22):4605–13.PubMedGoogle Scholar
  86. 86.
    Mandler M, Neubuser A. FGF signaling is necessary for the specification of the odontogenic mesenchyme. Dev Biol 2001;240(2):548–59.PubMedGoogle Scholar
  87. 87.
    Vainio S, Karavanova I, Jowett A, Thesleff I. Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development. Cell 1993;75(1):45–58.PubMedGoogle Scholar
  88. 88.
    Tucker AS, Matthews KL, Sharpe PT. Transformation of tooth type induced by inhibition of BMP signaling. Science 1998;282(5391):1136–8.PubMedGoogle Scholar
  89. 89.
    Trumpp A, Depew MJ, Rubenstein JL, Bishop JM, Martin GR. Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes Dev 1999;13(23):3136–48.PubMedGoogle Scholar
  90. 90.
    Ferguson CA, Tucker AS, Sharpe PT. Temporospatial cell interactions regulating mandibular and maxillary arch patterning. Development 2000;127(2):403–12.PubMedGoogle Scholar
  91. 91.
    St Amand TR, Zhang Y, Semina EV, Zhao X, Hu Y, Nguyen L, et al. Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage. Dev Biol 2000;217(2):323–32.PubMedGoogle Scholar
  92. 92.
    Peters H, Neubuser A, Kratochwil K, Balling R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev 1998;12(17):2735–47.PubMedGoogle Scholar
  93. 93.
    Ruch JV, Lesot H, Karcher-Djuricic V, Meyer JM, Mark M. Epithelial–mesenchymal interactions in tooth germs: mechanisms of differentiation. J Biol Buccale 1983;11(3):173–93.PubMedGoogle Scholar
  94. 94.
    Lechler T, Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 2005.Google Scholar
  95. 95.
    Thomas BL, Tucker AS, Qui M, Ferguson CA, Hardcastle Z, Rubenstein JL, et al. Role of Dlx-1 and Dlx-2 genes in patterning of the murine dentition. Development 1997;124(23):4811–8.PubMedGoogle Scholar
  96. 96.
    Bei M, Maas R. FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Development 1998;125(21):4325–33.PubMedGoogle Scholar
  97. 97.
    Kettunen P, Karavanova I, Thesleff I. Responsiveness of developing dental tissues to fibroblast growth factors: expression of splicing alternatives of FGFR1, -2, -3, and of FGFR4; and stimulation of cell proliferation by FGF-2, -4, -8, and -9. Dev Genet 1998;22(4):374–85.PubMedGoogle Scholar
  98. 98.
    Pispa J, Jung HS, Jernvall J, Kettunen P, Mustonen T, Tabata MJ, et al. Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF. Dev Biol 1999;216(2):521–34.PubMedGoogle Scholar
  99. 99.
    Kangas AT, Evans AR, Thesleff I, Jernvall J. Nonindependence of mammalian dental characters. Nature 2004;432(7014):211–4.PubMedGoogle Scholar
  100. 100.
    Mustonen T, Pispa J, Mikkola ML, Pummila M, Kangas AT, Pakkasjarvi L, et al. Stimulation of ectodermal organ development by Ectodysplasin-A1. Dev Biol 2003;259(1):123–36.PubMedGoogle Scholar
  101. 101.
    Zhang Q, Murcia NS, Chittenden LR, Richards WG, Michaud EJ, Woychik RP, et al. Loss of the Tg737 protein results in skeletal patterning defects. Dev Dyn 2003;227(1):78–90.PubMedGoogle Scholar
  102. 102.
    Hardcastle Z, Mo R, Hui CC, Sharpe PT. The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development 1998;125(15):2803–11.PubMedGoogle Scholar
  103. 103.
    Cobourne MT, Hardcastle Z, Sharpe PT. Sonic hedgehog regulates epithelial proliferation and cell survival in the developing tooth germ. J Dent Res 2001;80(11):1974–9.PubMedGoogle Scholar
  104. 104.
    Dassule HR, Lewis P, Bei M, Maas R, McMahon AP. Sonic hedgehog regulates growth and morphogenesis of the tooth. Development 2000;127(22):4775–85.PubMedGoogle Scholar
  105. 105.
    Gritli-Linde A, Bei M, Maas R, Zhang XM, Linde A, McMahon AP. Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization. Development 2002;129(23):5323–37.PubMedGoogle Scholar
  106. 106.
    Ohazama A, Hu Y, Schmidt-Ullrich R, Cao Y, Scheidereit C, Karin M, et al. A dual role for ikkalpha in tooth development. Dev Cell 2004;6(2):219–27.PubMedGoogle Scholar
  107. 107.
    Vaahtokari A, Aberg T, Jernvall J, Keranen S, Thesleff I. The enamel knot as a signaling center in the developing mouse tooth. Mech Dev 1996;54(1):39–43.PubMedGoogle Scholar
  108. 108.
    Chen Y, Bei M, Woo I, Satokata I, Maas R. Msx1 controls inductive signaling in mammalian tooth morphogenesis. Development 1996;122(10):3035–44.PubMedGoogle Scholar
  109. 109.
    Bei M, Kratochwil K, Maas RL. BMP4 rescues a non-cell-autonomous function of Msx1 in tooth development. Development 2000;127(21):4711–8.PubMedGoogle Scholar
  110. 110.
    Jernvall J, Aberg T, Kettunen P, Keranen S, Thesleff I. The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Development 1998;125(2):161–9.PubMedGoogle Scholar
  111. 111.
    Kratochwil K, Galceran J, Tontsch S, Roth W, Grosschedl R. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes Dev 2003;16(24):3173–85.Google Scholar
  112. 112.
    D’Souza RN, Aberg T, Gaikwad J, Cavender A, Owen M, Karsenty G, et al. Cbfa1 is required for epithelial–mesenchymal interactions regulating tooth development in mice. Development 1999;126(13):2911–20.PubMedGoogle Scholar
  113. 113.
    Aberg T, Wang XP, Kim JH, Yamashiro T, Bei M, Rice R, et al. Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Dev Biol 2004;270(1):76–93.PubMedGoogle Scholar
  114. 114.
    Jernvall J, Kettunen P, Karavanova I, Martin LB, Thesleff I. Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. Int J Dev Biol 1994;38(3):463–9.PubMedGoogle Scholar
  115. 115.
    Ohazama A, Modino SA, Miletich I, Sharpe PT. Stem-cell-based tissue engineering of murine teeth. J Dent Res 2004;83(7):518–22.PubMedCrossRefGoogle Scholar
  116. 116.
    Gallego MI, Beachy PA, Hennighausen L, Robinson GW. Differential requirements for shh in mammary tissue and hair follicle morphogenesis. Dev Biol 2002;249(1):131–9.PubMedGoogle Scholar
  117. 117.
    Lin CR, Kioussi C, O’Connell S, Briata P, Szeto D, Liu F, et al. Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 1999;401(6750):279–82.PubMedGoogle Scholar
  118. 118.
    Brakebusch C, Grose R, Quondamatteo F, Ramirez A, Jorcano JL, Pirro A, et al. Skin and hair follicle integrity is crucially dependent on beta 1 integrin expression on keratinocytes. EMBO J 2000;19(15):3990–4003.PubMedGoogle Scholar
  119. 119.
    Raghavan S, Bauer C, Mundschau G, Li Q, Fuchs E. Conditional ablation of beta1 integrin in skin. Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J Cell Biol 2000;150(5):1149–60.PubMedGoogle Scholar
  120. 120.
    Vasioukhin V, Bauer C, Degenstein L, Wise B, Fuchs E. Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin. Cell 2001;104(4):605–17.PubMedGoogle Scholar
  121. 121.
    Nanba D, Hieda Y, Nakanishi Y. Remodeling of desmosomal and hemidesmosomal adhesion systems during early morphogenesis of mouse pelage hair follicles. J Invest Dermatol 2000;114(1):171–7.PubMedGoogle Scholar
  122. 122.
    Nanba D, Nakanishi Y, Hieda Y. Changes in adhesive properties of epithelial cells during early morphogenesis of the mammary gland. Dev Growth Differ 2001;43(5):535–44.PubMedGoogle Scholar
  123. 123.
    Ida M, Nakamura T, Utsunomiya J. Osteomatous changes and tooth abnormalities found in the jaw of patients with adenomatosis coli. Oral Surg Oral Med Oral Pathol 1981;52(1):2–11.PubMedGoogle Scholar
  124. 124.
    Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991;253(5020):665–9.PubMedGoogle Scholar
  125. 125.
    Lammi L, Arte S, Somer M, Jarvinen H, Lahermo P, Thesleff I, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 2004;74(5):1043–50.PubMedGoogle Scholar
  126. 126.
    Chan EF, Gat U, McNiff JM, Fuchs E. A common human skin tumour is caused by activating mutations in beta- catenin. Nat Genet 1999;21(4):410–3.PubMedGoogle Scholar
  127. 127.
    Brennan KR, Brown AM. Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia 2004;9(2):119–31.PubMedGoogle Scholar
  128. 128.
    Dillon C, Spencer-Dene B, Dickson C. A crucial role for fibroblast growth factor signaling in embryonic mammary gland development. J Mammary Gland Biol Neoplasia 2004;9(2):207–15.PubMedGoogle Scholar
  129. 129.
    Sternlicht MD. Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res 2006;8(1):201.PubMedGoogle Scholar
  130. 130.
    van Bokhoven H, Hamel BC, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PH, et al. p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand–split foot malformation suggest a genotype–phenotype correlation. Am J Hum Genet 2001;69(3):481–92.PubMedGoogle Scholar
  131. 131.
    van Bokhoven H, McKeon F. Mutations in the p53 homolog p63: allele-specific developmental syndromes in humans. Trends Mol Med 2002;8(3):133–9.PubMedGoogle Scholar
  132. 132.
    Kere J, Srivastava AK, Montonen O, Zonana J, Thomas N, Ferguson B, et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 1996;13(4):409–16.PubMedGoogle Scholar
  133. 133.
    Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 1999;22(4):366–9.PubMedGoogle Scholar
  134. 134.
    Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85(6):841–51.PubMedGoogle Scholar
  135. 135.
    Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272(5268):1668–71.PubMedGoogle Scholar
  136. 136.
    Unden AB, Holmberg E, Lundh-Rozell B, Stahle-Backdahl M, Zaphiropoulos PG, Toftgard R, et al. Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation. Cancer Res 1996;56(20):4562–5.PubMedGoogle Scholar
  137. 137.
    Markey AC, Lane EB, Macdonald DM, Leigh IM. Keratin expression in basal cell carcinomas. Br J Dermatol 1992;126(2):154–60.PubMedGoogle Scholar
  138. 138.
    Jih DM, Lyle S, Elenitsas R, Elder DE, Cotsarelis G. Cytokeratin 15 expression in trichoepitheliomas and a subset of basal cell carcinomas suggests they originate from hair follicle stem cells. J Cutan Pathol 1999;26(3):113–8.PubMedGoogle Scholar
  139. 139.
    Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 1996;14(1):78–81.PubMedGoogle Scholar
  140. 140.
    Zhang L, Chen XM, Sun ZJ, Bian Z, Fan MW, Chen Z. Epithelial expression of SHH signaling pathway in odontogenic tumors. Oral Oncol;2005.Google Scholar
  141. 141.
    Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, et al. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 1997;16(3):311–5.PubMedGoogle Scholar
  142. 142.
    Idrees F, Bloch-Zupan A, Free SL, Vaideanu D, Thompson PJ, Ashley P, et al. A novel homeobox mutation in the PITX2 gene in a family with Axenfeld–Rieger syndrome associated with brain, ocular, and dental phenotypes. Am J Med Genet B Neuropsychiatr Genet;2006.Google Scholar
  143. 143.
    Harada H, Toyono T, Toyoshima K, Yamasaki M, Itoh N, Kato S, et al. FGF10 maintains stem cell compartment in developing mouse incisors. Development 2002;129(6):1533–41.PubMedGoogle Scholar
  144. 144.
    Satokata I, Maas R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet 1994;6(4):348–56.PubMedGoogle Scholar
  145. 145.
    Ma L, Liu J, Wu T, Plikus M, Jiang TX, Bi Q, et al. ‘Cyclic alopecia’ in Msx2 mutants: defects in hair cycling and hair shaft differentiation. Development 2003;130(2):379–89.PubMedGoogle Scholar
  146. 146.
    Bei M, Stowell S, Maas R. Msx2 controls ameloblast terminal differentiation. Dev Dyn 2004;231(4):758–65.PubMedGoogle Scholar
  147. 147.
    Hansen LA, Alexander N, Hogan ME, Sundberg JP, Dlugosz A, Threadgill DW, et al. Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am J Pathol 1997;150(6):1959–75.PubMedGoogle Scholar
  148. 148.
    Luetteke NC, Phillips HK, Qiu TH, Copeland NG, Earp HS, Jenkins NA, et al. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev 1994;8(4):399–413.PubMedGoogle Scholar
  149. 149.
    Matzuk MM, Kumar TR, Vassalli A, Bickenbach JR, Roop DR, Jaenisch R, et al. Functional analysis of activins during mammalian development. Nature 1995;374(6520):354–6.PubMedGoogle Scholar
  150. 150.
    Ferguson CA, Tucker AS, Christensen L, Lau AL, Matzuk MM, Sharpe PT. Activin is an essential early mesenchymal signal in tooth development that is required for patterning of the murine dentition. Genes Dev 1998;12(16):2636–49.PubMedGoogle Scholar
  151. 151.
    Wang XP, Suomalainen M, Jorgez CJ, Matzuk MM, Werner S, Thesleff I. Follistatin regulates enamel patterning in mouse incisors by asymmetrically inhibiting BMP signaling and ameloblast differentiation. Dev Cell 2004;7(5):719–30.PubMedGoogle Scholar
  152. 152.
    Wang XP, Suomalainen M, Jorgez CJ, Matzuk MM, Wankell M, Werner S, et al. Modulation of activin/bone morphogenetic protein signaling by follistatin is required for the morphogenesis of mouse molar teeth. Dev Dyn 2004;231(1):98–108.PubMedGoogle Scholar
  153. 153.
    Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 2005;1(4):e53.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  1. 1.Developmental Biology Program, Institute of BiotechnologyUniversity of HelsinkiHelsinkiFinland
  2. 2.Departments of Dermatology and Cell and Developmental BiologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Department of DermatologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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