Skip to main content
Log in

IVD Development: Nucleus Pulposus Development and Sclerotome Specification

  • Intervertebral Disk Degeneration and Regeneration (MV Risbud, Section Editor)
  • Published:
Current Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Intervertebral discs (IVD) are derived from embryonic notochord and sclerotome. The nucleus pulposus is derived from notochord while other connective tissues of the spine are derived from sclerotome. This manuscript will review the past 5 years of research into IVD development.

Recent Findings

Over the past several years, advances in understanding the step-wise process that govern development of the nucleus pulposus and the annulus fibrosus have been made. Generation of tissues from induced or embryonic stem cells into nucleus pulposus and paraxial mesoderm derived tissues has been accomplished in vitro using pathways identified in normal development. A balance between BMP and TGF-ß signaling as well as transcription factors including Pax1/Pax9, Mkx, and Nkx3.2 appear to be very important for cell fate decisions generating tissues of the IVD.

Summary

Understanding how the IVD develops will provide the foundation for future repair, regeneration, and tissue engineering strategies for IVD disease.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. Paavola LG, Wilson DB, Center EM. Histochemistry of the developing notochord, perichordal sheath and vertebrae in Danforth’s short-tail (sd) and normal C57BL/6 mice. J Embryol Exp Morphol. 1980;55:227–45.

    PubMed  CAS  Google Scholar 

  2. Theiler K. Vertebral malformations. Adv Anat Embryol Cell Biol. 1988;112:1–99.

    Article  PubMed  CAS  Google Scholar 

  3. Rufai A, Benjamin M, Ralphs JR. The development of fibrocartilage in the rat intervertebral disc. Anat Embryol (Berl). 1995;192(1):53–62.

    Article  CAS  Google Scholar 

  4. Christ B, Huang R, Scaal M. Amniote somite derivatives. Dev Dyn: Off Publ Am Assoc Anatomists. 2007;236(9):2382–96. https://doi.org/10.1002/dvdy.21189.

    Article  CAS  Google Scholar 

  5. Christ B, Huang R, Wilting J. The development of the avian vertebral column. Anat Embryol. 2000;202(3):179–94.

    Article  PubMed  CAS  Google Scholar 

  6. Monsoro-Burq AH. Sclerotome development and morphogenesis: when experimental embryology meets genetics. Int J Dev Biol. 2005;49(2–3):301–8. https://doi.org/10.1387/ijdb.041953am.

    Article  PubMed  CAS  Google Scholar 

  7. Salisbury JR. The pathology of the human notochord. J Pathol. 1993;171(4):253–5. https://doi.org/10.1002/path.1711710404.

    Article  PubMed  CAS  Google Scholar 

  8. Stemple DL. Structure and function of the notochord: an essential organ for chordate development. Development. 2005;132(11):2503–12. https://doi.org/10.1242/dev.01812.

    Article  PubMed  CAS  Google Scholar 

  9. • Imuta Y, Koyama H, Shi D, Eiraku M, Fujimori T, Sasaki H. Mechanical control of notochord morphogenesis by extra-embryonic tissues in mouse embryos. Mech Dev. 2014;132:44–58. https://doi.org/10.1016/j.mod.2014.01.004. This study describes the importance of mechanical forces during notochord morphogenesis. This demonstrates that cell bevahior can be affected by mechanical force during embryongenesis

    Article  PubMed  CAS  Google Scholar 

  10. Adams DS, Keller R, Koehl MA. The mechanics of notochord elongation, straightening and stiffening in the embryo of Xenopus laevis. Development. 1990;110(1):115–30.

    PubMed  CAS  Google Scholar 

  11. Christ B, Huang R, Scaal M. Formation and differentiation of the avian sclerotome. Anat Embryol (Berl). 2004;208(5):333–50.

    Article  PubMed  Google Scholar 

  12. Stockdale FE, Nikovits W Jr, Christ B. Molecular and cellular biology of avian somite development. Dev Dyn. 2000;219(3):304–21.

    Article  PubMed  CAS  Google Scholar 

  13. Arendt D, Nubler-Jung K. Rearranging gastrulation in the name of yolk: evolution of gastrulation in yolk-rich amniote eggs. Mech Dev. 1999;81(1–2):3–22.

    Article  PubMed  CAS  Google Scholar 

  14. Mikawa T, Poh AM, Kelly KA, Ishii Y, Reese DE. Induction and patterning of the primitive streak, an organizing center of gastrulation in the amniote. Dev Dyn: Off Publ Am Assoc Anatomists. 2004;229(3):422–32. https://doi.org/10.1002/dvdy.10458.

    Article  Google Scholar 

  15. Tam PP, Behringer RR. Mouse gastrulation: the formation of a mammalian body plan. Mech Dev. 1997;68(1–2):3–25.

    Article  PubMed  CAS  Google Scholar 

  16. Pourquie O. Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell. 2011;145(5):650–63. https://doi.org/10.1016/j.cell.2011.05.011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Brand-Saberi B, Christ B. Evolution and development of distinct cell lineages derived from somites. Curr Top Dev Biol. 2000;48:1–42.

    PubMed  CAS  Google Scholar 

  18. Cooke J, Zeeman EC. A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. J Theor Biol. 1976;58(2):455–76.

    Article  PubMed  CAS  Google Scholar 

  19. Ferrer-Vaquer A, Viotti M, Hadjantonakis AK. Transitions between epithelial and mesenchymal states and the morphogenesis of the early mouse embryo. Cell Adhes Migr. 2010;4(3):447–57.

    Article  Google Scholar 

  20. Mittapalli VR, Huang R, Patel K, Christ B, Scaal M. Arthrotome: a specific joint forming compartment in the avian somite. Dev Dyn: Off Publ Am Assoc Anatomists. 2005;234(1):48–53. https://doi.org/10.1002/dvdy.20502.

    Article  Google Scholar 

  21. Kalcheim C, Ben-Yair R. Cell rearrangements during development of the somite and its derivatives. Curr Opin Genet Dev. 2005;15(4):371–80. https://doi.org/10.1016/j.gde.2005.05.004.

    Article  PubMed  CAS  Google Scholar 

  22. Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature. 1996;383(6599):407–13. https://doi.org/10.1038/383407a0.

    Article  PubMed  CAS  Google Scholar 

  23. Borycki AG, Mendham L, Emerson CP Jr. Control of somite patterning by sonic hedgehog and its downstream signal response genes. Development (Cambridge, England). 1998;125(4):777–90.

    CAS  Google Scholar 

  24. Dockter JL. Sclerotome induction and differentiation. Curr Top Dev Biol. 2000;48:77–127.

    Article  PubMed  CAS  Google Scholar 

  25. Fan CM, Tessier-Lavigne M. Patterning of mammalian somites by surface ectoderm and notochord: evidence for sclerotome induction by a hedgehog homolog. Cell. 1994;79(7):1175–86.

    Article  PubMed  CAS  Google Scholar 

  26. van den Akker GGH, Koenders MI, van de Loo FAJ, van Lent P, Blaney Davidson E, van der Kraan PM. Transcriptional profiling distinguishes inner and outer annulus fibrosus from nucleus pulposus in the bovine intervertebral disc. European spine journal: official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research. Society. 2017;26(8):2053–62. https://doi.org/10.1007/s00586-017-5150-3.

    Article  Google Scholar 

  27. Smits P, Li P, Mandel J, Zhang Z, Deng JM, Behringer RR, et al. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev Cell. 2001;1(2):277–90.

    Article  PubMed  CAS  Google Scholar 

  28. Choi KS, Harfe BD. Hedgehog signaling is required for formation of the notochord sheath and patterning of nuclei pulposi within the intervertebral discs. Proc Natl Acad Sci U S A. 2011;108(23):9484–9. https://doi.org/10.1073/pnas.1007566108.

    Article  PubMed  PubMed Central  Google Scholar 

  29. • Bhalla S, Lin KH, Tang SY. Postnatal development of the murine notochord remnants quantified by high-resolution contrast-enhanced MicroCT. Sci Rep. 2017;7(1):13361. https://doi.org/10.1038/s41598-017-13446-5. This work describes a new imaging technique to visualize embryonic notochord development. Techniques aimed at imaging embryonic tissue can help in understanding developmental processes and potentially diagnosing disease in utero

  30. •• van den Akker GG, Surtel DA, Cremers A, Hoes MF, Caron MM, Richardson SM, et al. EGR1 controls divergent cellular responses of distinctive nucleus pulposus cell types. BMC Musculoskelet Disord. 2016;17:124. https://doi.org/10.1186/s12891-016-0979-x. This study describes how different NP populations in the adult respond to inflammatory stimuli by way of a specific protein. This study confirms the heterogenous nature of the adult NP population and gives insight into how to study the NP’s response to inflammatory stimuli during degeneration

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. •• Richardson SM, Ludwinski FE, Gnanalingham KK, Atkinson RA, Freemont AJ, Hoyland JA. Notochordal and nucleus pulposus marker expression is maintained by sub-populations of adult human nucleus pulposus cells through aging and degeneration. Sci Rep. 2017;7(1):1501. https://doi.org/10.1038/s41598-017-01567-w. This project focuses on determining whether notochordal and NP markers are expressed during aging or disc degeneration. This is the first study to show that notochordal and NP markers are still expressed regardless of age or stage of disc degeneration

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. •• Peck SH, McKee KK, Tobias JW, Malhotra NR, Harfe BD, Smith LJ. Whole transcriptome analysis of notochord-derived cells during embryonic formation of the nucleus pulposus. Sci Rep. 2017;7(1):10504. https://doi.org/10.1038/s41598-017-10692-5. This study compares notochordal gene expression at two different developmental stages en route to the formation of the NP. This is the first study to map the notochordal cell transcriptome at different stages of development

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. •• Tang R, Jing L, Willard VP, Wu CL, Guilak F, Chen J, et al. Differentiation of human induced pluripotent stem cells into nucleus pulposus-like cells. Stem Cell Res Ther. 2018;9(1):61. https://doi.org/10.1186/s13287-018-0797-1. A new protocol that uses cues learned from developmental processes is described to differentiate human iPSCs into NP-like cell

    Article  PubMed  PubMed Central  Google Scholar 

  34. •• Merceron C, Mangiavini L, Robling A, Wilson TL, Giaccia AJ, Shapiro IM, et al. Loss of HIF-1alpha in the notochord results in cell death and complete disappearance of the nucleus pulposus. PLoS One. 2014;9(10):e110768. https://doi.org/10.1371/journal.pone.0110768. This study describes a novel role for HIF-1α in the development of the NP from the embryonic notochord. This is the first study to report such a role for HIF-1α in NP development

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Lenas P, Luyten FP, Doblare M, Nicodemou-Lena E, Lanzara AE. Modularity in developmental biology and artificial organs: a missing concept in tissue engineering. Artif Organs. 2011;35(6):656–62. https://doi.org/10.1111/j.1525-1594.2010.01135.x.

    Article  PubMed  Google Scholar 

  36. Lenas P, Moos M, Luyten FP. Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part II: from genes to networks: tissue engineering from the viewpoint of systems biology and network science. Tissue Eng Part B Rev. 2009;15(4):395–422. https://doi.org/10.1089/ten.TEB.2009.0461.

    Article  PubMed  CAS  Google Scholar 

  37. Lenas P, Moos M, Luyten FP. Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part I: from three-dimensional cell growth to biomimetics of in vivo development. Tissue Eng Part B Rev. 2009;15(4):381–94. https://doi.org/10.1089/ten.TEB.2008.0575.

    Article  PubMed  Google Scholar 

  38. Gadjanski I, Spiller K, Vunjak-Novakovic G. Time-dependent processes in stem cell-based tissue engineering of articular cartilage. Stem Cell Rev. 2011;8:863–81. https://doi.org/10.1007/s12015-011-9328-5.

    Article  CAS  Google Scholar 

  39. Aulehla A, Pourquie O. Signaling gradients during paraxial mesoderm development. Cold Spring Harb Perspect Biol. 2010;2(2):a000869. https://doi.org/10.1101/cshperspect.a000869.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Yamaguchi TP, Takada S, Yoshikawa Y, Wu N, McMahon AP. T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification. Genes Dev. 1999;13(24):3185–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. •• Zhao J, Li S, Trilok S, Tanaka M, Jokubaitis-Jameson V, Wang B, et al. Small molecule-directed specification of sclerotome-like chondroprogenitors and induction of a somitic chondrogenesis program from embryonic stem cells. Development (Cambridge, England). 2014;141(20):3848–58. https://doi.org/10.1242/dev.105981. This paper utilizes synthetic inhibitors to mimic the developmental pathways required to differentiate mesenychmal stem cells into paraxial mesoderm and sclerotome-like cells

    Article  CAS  Google Scholar 

  42. •• Craft AM, Ahmed N, Rockel JS, Baht GS, Alman BA, Kandel RA, et al. Specification of chondrocytes and cartilage tissues from embryonic stem cells. Development. 2013;140(12):2597–610. https://doi.org/10.1242/dev.087890. This paper dervies chondrogenic mesoderm from embryonic stem cells with the intention to utilize the derived tissue for cartilage replacement therapy

    Article  PubMed  CAS  Google Scholar 

  43. •• Loh KM, Chen A, Koh PW, Deng TZ, Sinha R, Tsai JM, et al. Mapping the pairwise choices leading from pluripotency to human bone, heart, and Other Mesoderm Cell Types. Cell. 2016;166(2):451–67. https://doi.org/10.1016/j.cell.2016.06.011. This paper determined the extrinsic signals required to stimulate stem cell differentation from pluripotency to 12 different human mesoderm lineages

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Tanaka T, Uhthoff HK. Significance of resegmentation in the pathogenesis of vertebral body malformation. Acta Orthop Scand. 1981;52(3):331–8.

    Article  PubMed  CAS  Google Scholar 

  45. Huang R, Zhi Q, Brand-Saberi B, Christ B. New experimental evidence for somite resegmentation. Anat Embryol. 2000;202(3):195–200.

    Article  PubMed  CAS  Google Scholar 

  46. Bagnall KM, Higgins SJ, Sanders EJ. The contribution made by a single somite to the vertebral column: experimental evidence in support of resegmentation using the chick-quail chimaera model. Development (Cambridge, England). 1988;103(1):69–85.

    CAS  Google Scholar 

  47. Goldstein RS, Kalcheim C. Determination of epithelial half-somites in skeletal morphogenesis. Development (Cambridge, England). 1992;116(2):441–5.

    CAS  Google Scholar 

  48. • Umegaki M, Miyao Y, Sasaki M, Yoshimura K, Iwatsuki K, Yoshimine T. Report of a familial case of proatlas segmentation abnormality with late clinical onset. J Clin Neurosci : Off J Neurosurg Soc Australas. 2017;39:79–81. https://doi.org/10.1016/j.jocn.2016.12.010. This paper suggests there maybe familial factors associated with Proatlas Segmentation Anomalies (PSA), which has not previously been reported

    Article  Google Scholar 

  49. • Spittank H, Goehmann U, Hage H, Sacher R. Persistent proatlas with additional segmentation of the craniovertebral junction—the Tsuang-Goehmann-Malformation. J Radiol Case Rep. 2016;10(10):15–23. https://doi.org/10.3941/jrcr.v10i10.2890. This paper discovered a new cervical spine dysplasia caused by Proatlas Segmentation Anomalies (PSA) that has not been previously characterized. The new dysplasia was named The Tsuang-Goehman Malformation

    Article  PubMed  PubMed Central  Google Scholar 

  50. • Muthukumar N. Proatlas segmentation anomalies: surgical management of five cases and review of the literature. J Pediatr Neurosci. 2016;11(1):14–9. https://doi.org/10.4103/1817-1745.181246. This paper discussed surgical strategies to treat Proatlas Segmentation Anomalies (PSA) in human patients

    Article  PubMed  PubMed Central  Google Scholar 

  51. Adeleye AO, Akinyemi RO. Cervical Klippel-Feil syndrome predisposing an elderly African man to central cord myelopathy following minor trauma. Afr Health Sci. 2010;10(3):302–4.

    PubMed  Google Scholar 

  52. Kawamura A, Koshida S, Takada S. Activator-to-repressor conversion of T-box transcription factors by the Ripply family of Groucho/TLE-associated mediators. Mol Cell Biol. 2008;28(10):3236–44. https://doi.org/10.1128/mcb.01754-07.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Neubuser A, Koseki H, Balling R. Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1. Dev Biol. 1995;170(2):701–16. https://doi.org/10.1006/dbio.1995.1248.

    Article  PubMed  CAS  Google Scholar 

  54. Leitges M, Neidhardt L, Haenig B, Herrmann BG, Kispert A. The paired homeobox gene Uncx4.1 specifies pedicles, transverse processes and proximal ribs of the vertebral column. Development (Cambridge, England). 2000;127(11):2259–67.

    CAS  Google Scholar 

  55. Morimoto M, Sasaki N, Oginuma M, Kiso M, Igarashi K, Aizaki K, Kanno J, Saga Y The negative regulation of Mesp2 by mouse Ripply2 is required to establish the rostro-caudal patterning within a somite. Development (Cambridge, England). 2007;134(8):1561–1569. doi:https://doi.org/10.1242/dev.000836.

  56. Bruggeman BJ, Maier JA, Mohiuddin YS, Powers R, Lo Y, Guimaraes-Camboa N, et al. Avian intervertebral disc arises from rostral sclerotome and lacks a nucleus pulposus: implications for evolution of the vertebrate disc. Dev Dyn : Off Publ Am Assoc Anatomists. 2012;241(4):675–83. https://doi.org/10.1002/dvdy.23750.

    Article  CAS  Google Scholar 

  57. •• Ward L, Evans SE. Stern CD. A resegmentation-shift model for vertebral patterning. J Anat. 2017;230(2):290–6. https://doi.org/10.1111/joa.12540. This paper proposes a new resegmentation model that elucidates the differential migration patterns of the sclerotome to form the neural arches of the spine

    Article  PubMed  Google Scholar 

  58. Sivakamasundari V, Lufkin T. Bridging the gap: understanding embryonic intervertebral disc development. Cell Dev Biol. 2012;1(2)

  59. •• Kuta A, Mao Y, Martin T, Ferreira de Sousa C, Whiting D, Zakaria S, et al. Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae. Development (Cambridge, England). 2016;143(13):2367–75. https://doi.org/10.1242/dev.131037. This paper determined that Fat4-Dchs1 signaling is an important pathway during vertebrae formation required for sclerotome cell proliferation and differentiation

    Article  PubMed Central  CAS  Google Scholar 

  60. Peters H, Wilm B, Sakai N, Imai K, Maas R, Balling R. Pax1 and Pax9 synergistically regulate vertebral column development. Development (Cambridge, England). 1999;126(23):5399–408.

    CAS  Google Scholar 

  61. •• Sivakamasundari V, Kraus P, Sun W, Hu X, Lim SL, Prabhakar S, et al. A developmental transcriptomic analysis of Pax1 and Pax9 in embryonic intervertebral disc development. Biol Open. 2017;6(2):187–99. https://doi.org/10.1242/bio.023218. This paper describes transcriptomic analysis in Pax1/Pax9+ cells, showing that Pax1/Pax9 change the important genes for pre-cartilage and IVD development and it is interconnected with BMP and TGFβ signaling

    Article  PubMed  CAS  Google Scholar 

  62. Lefebvre V, Behringer RR, de Crombrugghe B. L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Osteoarthr Cartil. 2001;9(Suppl A):S69–75.

    Article  PubMed  Google Scholar 

  63. Han Y, Lefebvre V. L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer. Mol Cell Biol. 2008;28(16):4999–5013. https://doi.org/10.1128/mcb.00695-08.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Murtaugh LC, Zeng L, Chyung JH, Lassar AB. The chick transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMP-dependent axial chondrogenesis. Dev Cell. 2001;1(3):411–22.

    Article  PubMed  CAS  Google Scholar 

  65. Sohn P, Cox M, Chen D, Serra R. Molecular profiling of the developing mouse axial skeleton: a role for Tgfbr2 in the development of the intervertebral disc. BMC Dev Biol. 2010;10:29. https://doi.org/10.1186/1471-213X-10-29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM. Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci U S A. 2005;102(14):5062–7. https://doi.org/10.1073/pnas.0500031102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. •• Ohba S, He X, Hojo H, McMahon AP. Distinct transcriptional programs underlie Sox9 regulation of the mammalian chondrocyte. Cell Rep. 2015;12(2):229–43. https://doi.org/10.1016/j.celrep.2015.06.013.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Sekiya I, Larson BL, Vuoristo JT, Reger RL, Prockop DJ. Comparison of effect of BMP-2, −4, and −6 on in vitro cartilage formation of human adult stem cells from bone marrow stroma. Cell Tissue Res. 2005;320(2):269–76. https://doi.org/10.1007/s00441-004-1075-3.

    Article  PubMed  CAS  Google Scholar 

  69. Ban G, Serra, R. Sclerotome fate is determined via relationship between TGFβ and Noggin. In Preparation. 2018.

  70. Mitter D, Krakow D, Farrington-Rock C, Meinecke P. Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father. Am J Med Genet A. 2008;146A(6):779–83. https://doi.org/10.1002/ajmg.a.32230.

    Article  PubMed  Google Scholar 

  71. •• Zieba J, Forlenza KN, Khatra JS, Sarukhanov A, Duran I, Rigueur D, et al. TGFbeta and BMP dependent cell fate changes due to loss of Filamin B produces disc degeneration and progressive vertebral fusions. PLoS Genet. 2016;12(3):e1005936. https://doi.org/10.1371/journal.pgen.1005936. This paper presents that the importance of Filamin B in IVD neonatal development and maintenance. Also, it shows the balance of BMP and TGFβ signaling is disrupted in AF cells of mice with loss of Filamin B.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Alkhatib B, Liu, C, Serra, R. Tgfbr2 is required in Acan-expressing cells for maintenance of the intervertebral and sternocostal joints. In Preparation 2018.

  73. Murchison ND, Price BA, Conner DA, Keene DR, Olson EN, Tabin CJ, et al. Regulation of tendon differentiation by scleraxis distinguishes force-transmitting tendons from muscle-anchoring tendons. Development. 2007;134(14):2697–708. https://doi.org/10.1242/dev.001933.

    Article  PubMed  CAS  Google Scholar 

  74. Schweitzer R, Chyung JH, Murtaugh LC, Brent AE, Rosen V, Olson EN, et al. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development. 2001;128(19):3855–66.

    PubMed  CAS  Google Scholar 

  75. •• Blitz E, Sharir A, Akiyama H, Zelzer E. Tendon-bone attachment unit is formed modularly by a distinct pool of Scx- and Sox9-positive progenitors. Development. 2013;140(13):2680–90. https://doi.org/10.1242/dev.093906. This paper describes cell linage analysis for tendon-bone attachment, showing SCX+/SOX9+ cells are progenitor cell of tendon-bone attachment unit

    Article  PubMed  CAS  Google Scholar 

  76. •• Sugimoto Y, Takimoto A, Akiyama H, Kist R, Scherer G, Nakamura T, et al. Scx+/Sox9+ progenitors contribute to the establishment of the junction between cartilage and tendon/ligament. Development. 2013;140(11):2280–8. https://doi.org/10.1242/dev.096354. This paper, combined with Ref71, presents that SCX+ /Sox9 + cells are progenitor cells to form junction between cartilage and tendon/ligament including AF. Specifically, it shows that Sox9 has important role for proper formation between oAF and iAF

    Article  PubMed  CAS  Google Scholar 

  77. •• Nakamichi R, Ito Y, Inui M, Onizuka N, Kayama T, Kataoka K, et al. Mohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs. Nat Commun. 2016;7:12503. https://doi.org/10.1038/ncomms12503. This paper demonstrates the importance of Mohawk for oAF formation. Particularly, it shows over-expreesion of Mohawk in mesenchymal cell promotes regeneration of oAF in disc degeneration model

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Aszodi A, Chan D, Hunziker E, Bateman JF, Fassler R. Collagen II is essential for the removal of the notochord and the formation of intervertebral discs. J Cell Biol. 1998;143(5):1399–412.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Furukawa T, Ito K, Nuka S, Hashimoto J, Takei H, Takahara M, et al. Absence of biglycan accelerates the degenerative process in mouse intervertebral disc. Spine. 2009;34(25):E911–7. https://doi.org/10.1097/BRS.0b013e3181b7c7ec.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Hayes AJ, Hughes CE, Ralphs JR, Caterson B. Chondroitin sulphate sulphation motif expression in the ontogeny of the intervertebral disc. Eur Cells Mater. 2011;21:1–14.

    Article  CAS  Google Scholar 

  81. Hayes AJ, Isaacs MD, Hughes C, Caterson B, Ralphs JR. Collagen fibrillogenesis in the development of the annulus fibrosus of the intervertebral disc. Eur Cells Mater. 2011;22:226–41.

    Article  CAS  Google Scholar 

  82. • Beckett MC, Ralphs JR, Caterson B, Hayes AJ. The transmembrane heparan sulphate proteoglycan syndecan-4 is involved in establishment of the lamellar structure of the annulus fibrosus of the intervertebral disc. Eur Cells Mater. 2015;30:69–88. This paper describes expression patterning of syndecan-4 in AF of rat, showing syndecan-4 could have important role in lamellar structure formation in oAF

    Article  CAS  Google Scholar 

  83. Choi Y, Chung H, Jung H, Couchman JR, Oh ES. Syndecans as cell surface receptors: unique structure equates with functional diversity. Matrix Biol : J Int Soc Matrix Biol 2011;30(2):93–99. doi:https://doi.org/10.1016/j.matbio.2010.10.006.

  84. Oldershaw RA, Baxter MA, Lowe ET, Bates N, Grady LM, Soncin F, et al. Directed differentiation of human embryonic stem cells toward chondrocytes. Nat Biotechnol. 2010;28(11):1187–94. https://doi.org/10.1038/nbt.1683.

    Article  PubMed  CAS  Google Scholar 

  85. Scotti C, Tonnarelli B, Papadimitropoulos A, Scherberich A, Schaeren S, Schauerte A, et al. Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering. Proc Natl Acad Sci U S A. 2010;107(16):7251–6. https://doi.org/10.1073/pnas.1000302107.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rosa Serra.

Ethics declarations

Conflict of Interest

Bashar Alkhatib, Ga I Ban, Sade Williams, and Rosa Serra declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Intervertebral Disk Degeneration and Regeneration

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alkhatib, B., Ban, G.I., Williams, S. et al. IVD Development: Nucleus Pulposus Development and Sclerotome Specification. Curr Mol Bio Rep 4, 132–141 (2018). https://doi.org/10.1007/s40610-018-0100-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40610-018-0100-3

Keywords

Navigation