Skip to main content
SpringerLink
Log in

Notch Signaling and the Developing Skeleton

  • Chapter
Notch Signaling in Embryology and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 727))

Abstract

Notch signaling is an important regulator of skeletogenesis at multiple developmental stages. The Notch signaling pathway is involved in the promotion of somite segmentation, patterning and differentiation into sclerotome pre-chondrogenic cells to allow for appropriate axial skeleton development. In addition, studies performed in vitro and in vivo demonstrate that Notch signaling suppresses chondrogenic and osteoblastic differentiation and negatively regulates osteoclast formation and proliferation. Through the use of in vitro and in vivo approaches, Notch signaling has been shown to regulate somitogenesis, chondrogenesis, osteoblastogenesis and osteoclastogenesis that ultimately affect skeletogenesis. Dysregulation of Notch signaling results in congenital skeletal malformations that could reveal therapeutic potential.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. de Crombrugghe B, Lefebvre V, Behringer RR et al. Transcriptional mechanisms of chondrocyte differentiation. Matrix Biol 2000; 19(5):389–394.

    Article  PubMed  Google Scholar 

  2. de Crombrugghe B, Lefebvre V, Nakashima K. Regulatory mechanisms in the pathways of cartilage and bone formation. Curr Opin Cell Biol 2001; 13(6):721–727.

    Article  PubMed  Google Scholar 

  3. Kovall RA. More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene 2008; 27(38):5099–5109.

    Article  PubMed  CAS  Google Scholar 

  4. Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 2003; 194(3):237–255.

    Article  PubMed  CAS  Google Scholar 

  5. Shifley ET, Cole SE. The vertebrate segmentation clock and its role in skeletal birth defects. Birth Defects Res C Embryo Today 2007; 81(2):121–133.

    Article  PubMed  CAS  Google Scholar 

  6. Gridley T. The long and short of it: somite formation in mice. Dev Dyn. 2006; 235(9):2330–2336.

    Article  PubMed  Google Scholar 

  7. Sewell W, Kusumi K. Genetic analysis of molecular oscillators in mammalian somitogenesis: clues for studies of human vertebral disorders. Birth Defects Res C Embryo Today 2007; 81(2):111–120.

    Article  PubMed  CAS  Google Scholar 

  8. Conlon RA, Reaume AG, Rossant J. Notch is required for the coordinate segmentation of somites. Development 1995; 121(5):1533–1545.

    PubMed  CAS  Google Scholar 

  9. Huppert SS, Le A, Schroeter EH et al. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 2000; 405(6789):966–970.

    Article  PubMed  CAS  Google Scholar 

  10. Oka C, Nakano T, Wakeham A et al. Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development 1995; 121(10):3291–3301.

    PubMed  CAS  Google Scholar 

  11. Donoviel DB, Hadjantonakis AK, Ikeda M et al. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 1999; 13(21):2801–2810.

    Article  PubMed  CAS  Google Scholar 

  12. Koizumi K, Nakajima M, Yuasa S et al. The role of presenilin 1 during somite segmentation. Development 2001; 128(8):1391–1402.

    PubMed  CAS  Google Scholar 

  13. Saga Y, Hata N, Koseki H et al. Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev 1997; 11(14):1827–1839.

    Article  PubMed  CAS  Google Scholar 

  14. Saga Y. Genetic rescue of segmentation defect in MesP2-deficient mice by MesP1 gene replacement. Mech Dev 1998; 75(1–2):53–66.

    Article  PubMed  CAS  Google Scholar 

  15. Hrabe de Angelis M, McIntyre J, 2nd, Gossler A. Maintenance of somite borders in mice requires the Delta homologue D111. Nature 1997; 386(6626):717–721.

    Article  PubMed  CAS  Google Scholar 

  16. Kusumi K, Sun ES, Kerrebrock AW et al. The mouse pudgy mutation disrupts Delta homologue D113 and initiation of early somite boundaries. Nat Genet 1998;19(3):274–278.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang N, Gridley T. Defects in somite formation in lunatic fringe-deficient mice. Nature 1998; 394(6691):374–377.

    Article  PubMed  CAS  Google Scholar 

  18. Evrard YA, Lun Y, Aulehla A et al. lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 1998; 394(6691):377–381.

    Article  PubMed  CAS  Google Scholar 

  19. Bessho Y, Sakata R, Komatsu S et al. Dynamic expression and essential functions of Hes7 in somite segmentation. Genes Dev 2001; 15(20):2642–2647.

    Article  PubMed  CAS  Google Scholar 

  20. Nakagawa O, Nakagawa M, Richardson JA et al. HRT1, HRT2 and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic and pharyngeal arch segments. Dev Biol 1999; 216(1):72–84.

    Article  PubMed  CAS  Google Scholar 

  21. Fischer A, Schumacher N, Maier M et al. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 2004; 18(8):901–911.

    Article  PubMed  CAS  Google Scholar 

  22. Leitges M, Neidhardt L, Haenig B et al. The paired homeobox gene Uncx4.1 specifies pedicles, transverse processes and proximal ribs of the vertebral column. Development 2000; 127(11):2259–2267.

    PubMed  CAS  Google Scholar 

  23. Mead TJ, Yutzey KE. Notch pathway regulation of chondrocyte differentiation and proliferation during appendicular and axial skeleton development. Proc Natl Acad Sci USA 2009; 106(34):14420–14425.

    Article  PubMed  CAS  Google Scholar 

  24. Lefebvre V, Smits P. Transcriptional control of chondrocyte fate and differentiation. Birth Defects Res 25. Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2002; 2(4):389–406.

    Article  Google Scholar 

  25. Hunziker EB, Schenk RK, Cruz-Orive LM. Quantitation of chondrocyte performance in growth-plate cartilage during longitudinal bone growth. J Bone Joint Surg Am 1987; 69(2):162–173.

    PubMed  CAS  Google Scholar 

  26. Shum L, Coleman CM, Hatakeyama Y et al. Morphogenesis and dysmorphogenesis of the appendicular skeleton. Birth Defects Res C Embryo Today 2003; 69(2):102–122.

    Article  PubMed  CAS  Google Scholar 

  27. Gerber HP, Vu TH, Ryan AM et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999; 5(6):623–628.

    Article  PubMed  CAS  Google Scholar 

  28. Kronenberg HM. Developmental regulation of the growth plate. Nature 2003; 423(6937):332–336.

    Article  PubMed  CAS  Google Scholar 

  29. Watanabe N, Tezuka Y, Matsuno K et al. Suppression of differentiation and proliferation of early chondrogenic cells by Notch. J Bone Miner Metab 2003; 21(6):344–352.

    Article  PubMed  CAS  Google Scholar 

  30. Nakanishi K, Chan YS, Ito K. Notch signaling is required for the chondrogenic specification of mouse mesencephalic neural crest cells. Mech Dev 2007; 124(3):190–203.

    Article  PubMed  CAS  Google Scholar 

  31. Fujimaki R, Toyama Y, Hozumi N et al. Involvement of Notch signaling in initiation of prechondrogenic condensation and nodule formation in limb bud micromass cultures. J Bone Miner Metab 2006; 24(3):191–198.

    Article  PubMed  CAS  Google Scholar 

  32. Dong Y, Jesse AM, Kohn A et al. RBPjkappa∼-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development. Development 2010; 137(9):1461–1471.

    Article  PubMed  CAS  Google Scholar 

  33. Oldershaw RA, Tew SR, Russell AM et al. Notch signaling through Jagged-1 is necessary to initiate chondrogenesis in human bone marrow stromal cells but must be switched off to complete chondrogenesis. Stem Cells 2008; 26(3):666–674.

    Article  PubMed  CAS  Google Scholar 

  34. Akiyama H, Chaboissier MC, Martin JF et al. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 2002; 16(21):2813–2828.

    Article  PubMed  CAS  Google Scholar 

  35. Grogan SP, Olee T, Hiraoka K et al. Repression of chondrogenesis through binding of notch signaling proteins HES-1 and HEY-1 to N-box domains in the COL2A1 enhancer site. Arthritis Rheum 2008; 58(9):2754–2763.

    Article  PubMed  Google Scholar 

  36. Crowe R, Zikherman J, Niswander L. Delta-1 negatively regulates the transition from prehypertrophic to hypertrophic chondrocytes during cartilage formation. Development 1999; 126(5):987–998.

    PubMed  CAS  Google Scholar 

  37. Hilton MJ, Tu X, Wu X et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 2008; 14(3):306–314.

    Article  PubMed  CAS  Google Scholar 

  38. Karlsson C, Brantsing C, Kageyama R et al. HES1 and HES5 Are Dispensable for Cartilage and Endochondral Bone Formation. Cells Tissues Organs 2010.

    Google Scholar 

  39. Deng ZL, Sharff KA, Tang N et al. Regulation of osteogenic differentiation during skeletal development. Front Biosci 2008; 13:2001–2021.

    Article  PubMed  CAS  Google Scholar 

  40. Akiyama H, Kim JE, Nakashima K et al. Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors. Proc Natl Acad Sci USA 2005; 102(41):14665–14670.

    Article  PubMed  CAS  Google Scholar 

  41. Shindo K, Kawashima N, Sakamoto K et al. Osteogenic differentiation of the mesenchymal progenitor cells, Kusa is suppressed by Notch signaling. Exp Cell Res 2003; 290(2):370–380.

    Article  PubMed  CAS  Google Scholar 

  42. Sciaudone M, Gazzerro E, Priest L et al. Notch 1 impairs osteoblastic cell differentiation. Endocrinology 2003; 144(12):5631–5639.

    Article  PubMed  CAS  Google Scholar 

  43. Zamurovic N, Cappellen D, Rohner D et al. Coordinated activation of notch, Wnt and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. J Biol Chem 2004; 279(36):37704–37715.

    Article  PubMed  CAS  Google Scholar 

  44. Zanotti S, Smerdel-Ramoya A, Stadmeyer L et al. Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology 2008; 149(8):3890–3899.

    Article  PubMed  CAS  Google Scholar 

  45. Deregowski V, Gazzerro E, Priest L et al. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling. J Biol Chem 2006; 281(10):6203–6210.

    Article  PubMed  CAS  Google Scholar 

  46. Engin F, Yao Z, Yang T et al. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 2008; 14(3):299–305.

    Article  PubMed  CAS  Google Scholar 

  47. Ducy P, Zhang R, Geoffroy V et al. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997; 89(5):747–754.

    Article  PubMed  CAS  Google Scholar 

  48. Otto F, Thornell AP, Crompton T et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997; 89(5):765–771.

    Article  PubMed  CAS  Google Scholar 

  49. Komori T, Yagi H, Nomura S et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89(5):755–764.

    Article  PubMed  CAS  Google Scholar 

  50. Tezuka K, Yasuda M, Watanabe N et al. Stimulation of osteoblastic cell differentiation by Notch. J Bone Miner Res 2002; 17(2):231–239.

    Article  PubMed  CAS  Google Scholar 

  51. Nobta M, Tsukazaki T, Shibata Y et al. Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. J Biol Chem 2005; 280(16):15842–15848.

    Article  PubMed  CAS  Google Scholar 

  52. Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet 2003; 4(8):638–649.

    Article  PubMed  CAS  Google Scholar 

  53. Yoshida H, Hayashi S, Kunisada T et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 1990; 345(6274):442–444.

    Article  PubMed  CAS  Google Scholar 

  54. Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89(2):309–319.

    Article  PubMed  CAS  Google Scholar 

  55. Yamada T, Yamazaki H, Yamane T et al. Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells. Blood 2003; 101(6):2227–2234.

    Article  PubMed  CAS  Google Scholar 

  56. Bai S, Kopan R, Zou W et al. NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem 2008; 283(10):6509–6518.

    Article  PubMed  CAS  Google Scholar 

  57. Fukushima H, Nakao A, Okamoto F et al. The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol 2008; 28(20):6402–6412.

    Article  PubMed  CAS  Google Scholar 

  58. Turnpenny PD, Alman B, Cornier AS et al. Abnormal vertebral segmentation and the notch signaling pathway in man. Dev Dyn 2007; 236(6):1456–1474.

    Article  PubMed  CAS  Google Scholar 

  59. Bulman MP, Kusumi K, Frayling TM et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet 2000; 24(4):438–441.

    Article  PubMed  CAS  Google Scholar 

  60. Dunwoodie SL, Clements M, Sparrow DB et al. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene D113 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development 2002; 129(7):1795–1806.

    PubMed  CAS  Google Scholar 

  61. Whittock NV, Sparrow DB, Wouters MA et al. Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet 2004; 74(6):1249–1254.

    Article  PubMed  CAS  Google Scholar 

  62. Sparrow DB, Chapman G, Wouters MA et al. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet 2006; 78(1):28–37.

    Article  PubMed  CAS  Google Scholar 

  63. Sparrow DB, Guillen-Navarro E, Fatkin D et al. Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis. Hum Mol Genet 2008; 17(23):3761–3766.

    Article  PubMed  CAS  Google Scholar 

  64. Sparrow DB, Sillence D, Wouters MA et al. Two novel missense mutations in HAIRY-ANDENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis. Eur J Hum Genet 2010.

    Google Scholar 

  65. Loomes KM, Stevens SA, O’Brien ML et al. D113 and Notch1 genetic interactions model axial segmental and craniofacial malformations of human birth defects. Dev Dyn 2007; 236(10):2943–2951.

    Article  PubMed  CAS  Google Scholar 

  66. Morales AV, Yasuda Y, Ish-Horowicz D. Periodic Lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to notch signaling. Dev Cell 2002; 3(1):63–74.

    Article  PubMed  CAS  Google Scholar 

  67. Li L, Krantz ID, Deng Y et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997; 16(3):243–251.

    Article  PubMed  CAS  Google Scholar 

  68. Oda T, Elkahloun AG, Pike BL et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997; 16(3):235–242.

    Article  PubMed  CAS  Google Scholar 

  69. McDaniell R, Warthen DM, Sanchez-Lara PA et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 2006; 79(1):169–173.

    Article  PubMed  CAS  Google Scholar 

  70. Olsen IE, Ittenbach RF, Rovner AJ et al. Deficits in size-adjusted bone mass in children with Alagille syndrome. J Pediatr Gastroenterol Nutr 2005; 40(1):76–82.

    Article  PubMed  Google Scholar 

  71. Xue Y, Gao X, Lindsell CE et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 1999; 8(5):723–730.

    Article  PubMed  CAS  Google Scholar 

  72. McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 2002; 129(4):1075–1082.

    PubMed  CAS  Google Scholar 

  73. Ishii H, Nakazawa M, Yoshino S et al. Expression of notch homologues in the synovium of rheumatoid arthritis and osteoarthritis patients. Rheumatol Int 2001; 21(1):10–14.

    Article  PubMed  CAS  Google Scholar 

  74. Karlsson C, Brantsing C, Egell S et al. Notch1, Jagged1 and HES5 are abundantly expressed in osteoarthritis. Cells Tissues Organs 2008; 188(3):287–298.

    Article  PubMed  CAS  Google Scholar 

  75. Khan IM, Palmer EA, Archer CW. Fibroblast growth factor-2 induced chondrocyte cluster formation in experimentally wounded articular cartilage is blocked by soluble Jagged-1. Osteoarthritis Cartilage 2010; 18(2):208–219.

    Article  PubMed  CAS  Google Scholar 

  76. Engin F, Bertin T, Ma O et al. Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum Mol Genet 2009; 18(8):1464–1470.

    Article  PubMed  CAS  Google Scholar 

  77. Zhang P, Yang Y, Zweidler-McKay PA et al. Critical role of notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res 2008; 14(10):2962–2969.

    Article  PubMed  CAS  Google Scholar 

  78. Tanaka M, Setoguchi T, Hirotsu M et al. Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br J Cancer 2009; 100(12):1957–1965.

    Article  PubMed  CAS  Google Scholar 

  79. Zhang P, Yang Y, Nolo R et al. Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness. Oncogene 2010; 29(20):2916–2926.

    Article  PubMed  CAS  Google Scholar 

  80. Hughes DP. How the NOTCH Pathway Contributes to the Ability of Osteosarcoma Cells to Metastasize. Cancer Treat Res 2010; 152:479–496.

    Article  Google Scholar 

  81. Nakamura E, Nguyen MT, Mackem S. Kinetics of tamoxifen-regulated Cre activity in mice using a cartilage-specific CreER(T) to assay temporal activity windows along the proximodistal limb skeleton. Dev Dyn 2006; 235(9):2603–2612.

    Article  PubMed  CAS  Google Scholar 

  82. Kamiya N, Ye L, Kobayashi T et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development 2008; 135(22):3801–3811.

    Article  PubMed  CAS  Google Scholar 

  83. Kawanami A, Matsushita T, Chan YY et al. Mice expressing GFP and CreER in osteochondro progenitor cells in the periosteum. Biochem Biophys Res Commun 2009; 386(3):477–482.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

    Timothy J. Mead & Katherine E. Yutzey

Authors
  1. Timothy J. Mead
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katherine E. Yutzey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katherine E. Yutzey .

Editor information

Editors and Affiliations

  1. Department of Dermatology, The Saarland University Hospital, Homburg, Germany

    Jörg Reichrath

  2. Department of Internal Medicine I, The Saarland University Hospital, Homburg, Germany

    Sandra Reichrath

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Mead, T.J., Yutzey, K.E. (2012). Notch Signaling and the Developing Skeleton. In: Reichrath, J., Reichrath, S. (eds) Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology, vol 727. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0899-4_9

Download citation

Publish with us

Policies and ethics

Search

Navigation