Skip to main content

Advertisement

SpringerLink
Log in

The role of matrix metalloproteinases in the morphogenesis of the cerebellar cortex

  • Original Article
  • Scientific Papers
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

The morphogenesis of the cerebellar cortex depends on intrinsic genetic programs as well as orchestrated cell-cell/ cell-extracellular matrix (ECM) interactions. The matrix metalloproteinase (MMP) family comprises of more than 20 members that catalyze the degradation of all the protein constituents of the ECM. These proteolytic endopeptidases mediate cell-cell/cell-ECM interactions by remodeling the ECM and modulating the activity of membrane-associated receptors. The activity of MMPs is negatively controlled by the tissue inhibitors of metalloproteinases (TIMPs). The MMPs and TIMPs regulate diverse neuronal functions including migration, process extension and synaptic plasticity. MMP-2,-3,-9, membrane type 5-MMP (MT5-MMP), TIMP-1, -2 and -3 are expressed in the developing cerebellum. The spatiotemporal pattern of expression/activity of these enzymes suggests that they play a role in the development of the cerebellar cortex. Blockage of MMP-2/-9 activity by specific inhibitors or blocking antibody, as well as using MMP-9 knock-out mice, clearly establishes that MMP-2/-9 participates in the regulation of morphogenesis of the cerebellum. The potential contributions of these enzymes to granule neuron migration, Purkinje cell dendritogenesis and synaptogenesis are discussed.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Altman J. Postnatal development of the cerebellar cortex in the rat. III. Maturation of the components of the granular layer. J Comp Neurol. 1972;145:465–513.

    Article  PubMed  CAS  Google Scholar 

  2. Altman J. Postnatal development of the cerebellar cortex in the rat. I. The external germinal layer and the transitional molecular layer. J Comp Neurol. 1972;145:353–97.

    Article  PubMed  CAS  Google Scholar 

  3. Altman J. Postnatal development of the cerebellar cortex in the rat. II. Phase in the maturation of Purkinje cells and of molecular layer. J Comp Neurol. 1972;145:399–463.

    Article  PubMed  CAS  Google Scholar 

  4. Sotelo C. Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol. 2004;72:295–339.

    Article  PubMed  CAS  Google Scholar 

  5. Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T. Regulation of matrix metalloproteinases: An overview. Mol Cell Biochem. 2003;253:269–85.

    Article  PubMed  CAS  Google Scholar 

  6. Nagase H, Woessner JF Jr. Matrix metalloproteinases. J Biol Chem. 1999;274:21491–4.

    Article  PubMed  CAS  Google Scholar 

  7. Dzwonek J, Rylski M, Kaczmarek L. Matrix metalloproteinases and their endogenous inhibitors in neuronal physiology of the adult brain. FEBS Lett. 2004;567:129–35.

    Article  PubMed  CAS  Google Scholar 

  8. Nagase H, Meng Q, Malinovskii V, Huang W, Chung L, Bode W, Maskos K, Brew K. Engineering of selective TIMPs. Ann NY Acad Sci. 1999;878:1–11.

    Article  PubMed  CAS  Google Scholar 

  9. Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. 1998;21:75–80.

    Article  PubMed  CAS  Google Scholar 

  10. Mandal M, Mandal A, Das S, Chakraborti T, Sajal C. Clinical implications of matrix metalloproteinases. Mol Cell Biochem. 2003;252:305–29.

    Article  PubMed  CAS  Google Scholar 

  11. Kaczmarek L, Lapinska-Dzwonek J, Szymczak S. Matrix metalloproteinases in the adult brain physiology: A link between c-Fos, AP-1 and remodeling of neuronal connections? EMBO J. 2002;21:6643–8.

    Article  PubMed  CAS  Google Scholar 

  12. Avolio C, Giuliani F, Liuzzi GM, Ruggieri M, Paolicelli D, Riccio P, Livrea P, Trojano M. Adhesion molecules and matrix metalloproteinases in Multiple Sclerosis: effects induced by Interferon-beta. Brain Res Bull. 2003;61:357–64.

    Article  PubMed  CAS  Google Scholar 

  13. Lo EH, Wang X, Cuzner ML. Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloproteinases. J Neurosci Res. 2002;69:1–9.

    Article  PubMed  CAS  Google Scholar 

  14. Rosenberg GA. Matrix metalloproteinases in brain injury. J Neurotrauma. 1995;12:833–42.

    Article  PubMed  CAS  Google Scholar 

  15. Wright JW, Masino AJ, Reichert JR, Turner GD, Meighan SE, Meighan PC, Harding JW. Ethanol-induced impairment of spatial memory and brain matrix metalloproteinases. Brain Res. 2003;963:252–61.

    Article  PubMed  CAS  Google Scholar 

  16. Miale IL, Sidman RL. An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp Neurol. 1961;4:277–96.

    Article  PubMed  CAS  Google Scholar 

  17. Rakic P. Neuron-glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electronmicroscopic study in Macacus Rhesus. J Comp Neurol. 1971;141:283–312.

    Article  PubMed  CAS  Google Scholar 

  18. Rakic P. Principles of neural cell migration. Experientia. 1990;46:882–91.

    Article  PubMed  CAS  Google Scholar 

  19. Huhtala P, Tuuttila A, Chow LT, Lohi J, Keski-Oja J, Tryggvason K. Complete structure of the human gene for 92-kDa type IV collagenase. Divergent regulation of expression for the 92-and 72-kilodalton enzyme genes in HT-1080 cells. J Biol Chem. 1991;266:16485–90.

    PubMed  CAS  Google Scholar 

  20. Agapova OA, Ricard CS, Salvador-Silva M, Hernandez MR. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human optic nerve head astrocytes. Glia. 2001;33:205–16.

    Article  PubMed  CAS  Google Scholar 

  21. Fager N, Jaworski DM. Differential spatial distribution and temporal regulation of tissue inhibitor of metalloproteinase mRNA expression during rat central nervous system development. Mech Dev. 2000;98:105–9.

    Article  PubMed  CAS  Google Scholar 

  22. Ferguson TA, Muir D. MMP-2 and MMP-9 increase the neurite-promoting potential of schwann cell basal laminae and are upregulated in degenerated nerve. Mol Cell Neurosci. 2000;16:157–67.

    Article  PubMed  CAS  Google Scholar 

  23. Frolichsthal-Schoeller P, Vescovi AL, Krekoski CA, Murphy G, Edwards DR, Forsyth P. Expression and modulation of matrix metalloproteinase-2 and tissue inhibitors of metalloproteinases in human embryonic CNS stem cells. Neuroreport. 1999;10:345–51.

    Article  PubMed  CAS  Google Scholar 

  24. Oh LY, Larsen PH, Krekoski CA, Edwards DR, Donovan F, Werb Z, Yong VW. Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes. J Neurosci. 1999;19:8464–75.

    PubMed  CAS  Google Scholar 

  25. Uhm JH, Dooley NP, Oh LY, Yong VW. Oligodendrocytes utilize a matrix metalloproteinase, MMP-9, to extend processes along an astrocyte extracellular matrix. Glia. 1998;22:53–63.

    Article  PubMed  CAS  Google Scholar 

  26. Ayoub AE, Cai TQ, Kaplan RA, Luo J. Developmental expression of matrix metalloproteinases 2 and 9 and their potential role in the histogenesis of the cerebellar cortex. J Comp Neurol. 2005;481:403–15.

    Article  PubMed  CAS  Google Scholar 

  27. Vaillant C, Didier-Bazes M, Hutter A, Belin MF, Thomasset N. Spatiotemporal expression patterns of metalloproteinases and their inhibitors in the postnatal developing rat cerebellum. J Neurosci. 1999;19:4994–5004.

    PubMed  CAS  Google Scholar 

  28. Vaillant C, Meissirel C, Mutin M, Belin MF, Lund LR, Thomasset N. MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum. Mol Cell Neurosci. 2003;24:395–408.

    Article  PubMed  CAS  Google Scholar 

  29. Yamada K, Watanabe M. Cytodifferentiation of Bergmann glia and its relationship with Purkinje cells. Anat Sci Int. 2002;77:94–108.

    Article  PubMed  Google Scholar 

  30. Forsyth PA, Wong H, Laing TD, Rewcastle NB, Morris DG, Muzik H, Leco KJ, Johnston RN, Brasher PM, Sutherland G, Edwards DR. Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer. 1999;79:1828–35.

    Article  PubMed  CAS  Google Scholar 

  31. Huppertz B, Kertschanska S, Demir AY, Frank HG, Kaufmann P. Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta. Cell Tissue Res. 1998;291:133–48.

    Article  PubMed  CAS  Google Scholar 

  32. Pittman RN, Williams AG. Neurite penetration into collagen gels requires Ca2+-dependent metalloproteinase activity. Dev Neurosci. 1989;11:41–51.

    Article  PubMed  CAS  Google Scholar 

  33. Szklarczyk A, Lapinska J, Rylski M, McKay RD, Kaczmarek L. Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J Neurosci. 2002;22:920–30.

    PubMed  CAS  Google Scholar 

  34. Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem. 1997;378:151–60.

    PubMed  CAS  Google Scholar 

  35. Hahn-Dantona E, Ramos-DeSimone N, Sipley J, Nagase H, French DL, Quigley JP. Activation of proMMP-9 by a plasmin/MMP-3 cascade in a tumor cell model. Regulation by tissue inhibitors of metalloproteinases. Ann NY Acad Sci. 1999;878:372–87.

    Article  PubMed  CAS  Google Scholar 

  36. Seeds NW, Basham ME, Haffke SP. Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene. Proc Natl Acad Sci USA. 1999;96:14118–23.

    Article  PubMed  CAS  Google Scholar 

  37. Lambert E, Dasse E, Haye B, Petitfrere E. TIMPs as multifacial proteins. Crit Rev Oncol Hematol. 2004;49:187–98.

    Article  PubMed  Google Scholar 

  38. Ahonen M, Poukkula M, Baker AH, Kashiwagi M, Nagase H, Eriksson JE, Kahari VM. Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. Oncogene. 2003;22:2121–34.

    Article  PubMed  CAS  Google Scholar 

  39. Blavier L, Henriet P, Imren S, Declerck YA. Tissue inhibitors of matrix metalloproteinases in cancer. Ann NY Acad Sci. 1999;878:108–19.

    Article  PubMed  CAS  Google Scholar 

  40. Hornebeck W. Down-regulation of tissue inhibitor of matrix metalloprotease-1 (TIMP-1) in aged human skin contributes to matrix degradation and impaired cell growth and survival. Pathol Biol (Paris). 2003;51:569–73.

    CAS  Google Scholar 

  41. Jiang Y, Goldberg ID, Shi YE. Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene. 2002;21:2245–52.

    Article  PubMed  CAS  Google Scholar 

  42. Polette M, Nawrocki B, Pintiaux A, Massenat C, Maquoi E, Volders L, Schaaps JP, Birembaut P, Foidart JM. Expression of gelatinases A and B and their tissue inhibitors by cells of early and term human placenta and gestational endometrium. Lab Invest. 1994;71:838–46.

    PubMed  CAS  Google Scholar 

  43. Apte SS, Olsen BR, Murphy G. The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Biol Chem. 1995;270:14313–18.

    Article  PubMed  CAS  Google Scholar 

  44. Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem. 1994;269:9352–60.

    PubMed  CAS  Google Scholar 

  45. Will H, Atkinson SJ, Butler GS, Smith B, Murphy G. The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3. J Biol Chem. 1996;271:17119–23.

    Article  PubMed  CAS  Google Scholar 

  46. Ahonen M, Baker AH, Kahari VM. Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res. 1998;58:2310–15.

    PubMed  CAS  Google Scholar 

  47. Hayashita-Kinoh H, Kinoh H, Okada A, Komori K, Itoh Y, Chiba T, Kajita M, Yana I, Seiki M. Membrane-type 5 matrix metalloproteinase is expressed in differentiated neurons and regulates axonal growth. Cell Growth Differ. 2001;12:573–80.

    PubMed  CAS  Google Scholar 

  48. Jaworski DM. Developmental regulation of membrane type-5 matrix metalloproteinase (MT5-MMP) expression in the rat nervous system. Brain Res. 2000;860:174–7.

    Article  PubMed  CAS  Google Scholar 

  49. Sekine-Aizawa Y, Hama E, Watanabe K, Tsubuki S, Kanai-Azuma M, Kanai Y, Arai H, Aizawa H, Iwata N, Saido TC. Matrix metalloproteinase (MMP) system in brain: identification and characterization of brain-specific MMP highly expressed in cerebellum. Eur J Neurosci. 2001;13:935–48.

    Article  PubMed  CAS  Google Scholar 

  50. Hager G, Dodt HU, Zieglgansberger W, Liesi P. Novel forms of neuronal migration in the rat cerebellum. J Neurosci Res. 1995;40:207–19.

    Article  PubMed  CAS  Google Scholar 

  51. Jaeger CB, Kapoor R, Llinas R. Cytology and organization of rat cerebellar organ cultures. Neuroscience. 1988;26:509–38.

    Article  PubMed  CAS  Google Scholar 

  52. Kunimoto M, Suzuki T. Migration of granule neurons in cerebellar organotypic cultures is impaired by methylmercury. Neurosci Lett. 1997;226:183–6.

    Article  PubMed  CAS  Google Scholar 

  53. Takacs J, Metzger F. Morphological study of organotypic cerebellar cultures. Acta Biol Hung. 2002;53:187–204.

    Article  PubMed  CAS  Google Scholar 

  54. Tanaka M, Tomita A, Yoshida S, Yano M, Shimizu H. Observation of the highly organized development of granule cells in rat cerebellar organotypic cultures. Brain Res. 1994;641:319–27.

    Article  PubMed  CAS  Google Scholar 

  55. Edmondson JC, Hatten ME. Glial-guided granule neuron migration in vitro: A high-resolution time-lapse video microscopic study. J Neurosci. 7:1928–34.

  56. Komuro H, Yacubova E, Yacubova E, Rakic P. Mode and tempo of tangential cell migration in the cerebellar external granular layer. J Neurosci. 2001;21:527–40.

    PubMed  CAS  Google Scholar 

  57. Zuo J, Ferguson TA, Hernandez YJ, Stetler-Stevenson WG, Muir D. Neuronal matrix metalloproteinase-2 degrades and inactivates a neurite-inhibiting chondroitin sulfate proteoglycan. J Neurosci. 1998;18:5203–11.

    PubMed  CAS  Google Scholar 

  58. Nordstrom LA, Lochner J, Yeung W, Ciment G. The metalloproteinase stromelysin-1 (transin) mediates PC12 cell growth cone invasiveness through basal laminae. Mol Cell Neurosci. 1995;6:56–68.

    Article  PubMed  CAS  Google Scholar 

  59. Webber CA, Hocking JC, Yong VW, Stange CL, McFarlane S. Metalloproteases and guidance of retinal axons in the developing visual system. J Neurosci. 2002;22: 8091–100.

    PubMed  CAS  Google Scholar 

  60. Anton ES, Cameron RS, Rakic P. Role of neuron-glial junctional domain proteins in the maintenance and termination of neuronal migration across the embryonic cerebral wall. J Neurosci. 1996;16:2283–93.

    PubMed  CAS  Google Scholar 

  61. Cameron RS, Ruffin JW, Cho NK, Cameron PL, Rakic P. Developmental expression, pattern of distribution, and effect on cell aggregation implicate a neuron-glial junctional domain protein in neuronal migration. J Comp Neurol. 1997;387: 467–88.

    Article  PubMed  CAS  Google Scholar 

  62. Fishell G, Hatten ME. Astrotactin provides a receptor system for CNS neuronal migration. Development. 1991; 113: 755–65.

    PubMed  CAS  Google Scholar 

  63. Fishman RB, Hatten ME. Multiple receptor systems promote CNS neural migration. J Neurosci. 1993;13:3485–95.

    PubMed  CAS  Google Scholar 

  64. Hatten ME. Central nervous system neuronal migration. Annu Rev Neurosci. 1999;22:511–39.

    Article  PubMed  CAS  Google Scholar 

  65. Komuro H, Yacubova E. Recent advances in cerebellar granule cell migration. Cell Mol Life Sci. 2003;60:1084–98.

    PubMed  CAS  Google Scholar 

  66. Rivas RJ, Hatten ME. Motility and cytoskeletal organization of migrating cerebellar granule neurons. J Neurosci. 1995;15:981–9.

    PubMed  CAS  Google Scholar 

  67. Yacubova E, Komuro H. Intrinsic program for migration of cerebellar granule cells in vitro. J Neurosci. 2002;22: 5966–81.

    PubMed  CAS  Google Scholar 

  68. Imai K, Shikata H, Okada Y. Degradation of vitronectin by matrix metalloproteinases-1, -2, -3, -7 and -9. FEBS Lett. 1995;369:249–51.

    Article  PubMed  CAS  Google Scholar 

  69. Levi E, Fridman R, Miao HQ, Ma YS, Yayon A, Vlodavsky I. Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc Natl Acad Sci USA. 1996;93:7069–74.

    Article  PubMed  CAS  Google Scholar 

  70. Yu Q, Stamenkovic I. Cell surface-localized matrix metallo-proteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14: 163–76.

    PubMed  Google Scholar 

  71. Oh LY, Yong VW. Astrocytes promote process outgrowth by adult human oligodendrocytes in vitro through interaction between bFGF and astrocyte extracellular matrix. Glia. 1996;17:237–53.

    Article  PubMed  CAS  Google Scholar 

  72. Uhm JH, Dooley NP, Villemure JG, Yong VW. Glioma invasion in vitro: Regulation by matrix metalloprotease-2 and protein kinase C. Clin Exp Metastasis. 1996;14:421–33.

    Article  PubMed  CAS  Google Scholar 

  73. Dvergsten CL, Fosmire GJ, Ollerich DA, Sandstead HH. Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. I. Impaired acquisition of granule cells. Brain Res. 1983;271:217–26.

    Article  PubMed  CAS  Google Scholar 

  74. Howard JD, Mottet NK. Effects of methylmercury on the morphogenesis of the rat cerebellum. Teratology. 1986;34: 89–95.

    Article  PubMed  CAS  Google Scholar 

  75. Sager PR, Doherty RA, Rodier PM. Effects of methylmercury on developing mouse cerebellar cortex. Exp Neurol. 1982;77:179–93.

    Article  PubMed  CAS  Google Scholar 

  76. de Souza AP, Gerlach RF, Line SR. Inhibition of human gingival gelatinases (MMP-2 and MMP-9) by metal salts. Dent Mater. 2000;16:103–08.

    Article  PubMed  Google Scholar 

  77. Sopata I, Wize J. A latent gelatin specific proteinase of human leucocytes and its activation. Biochim Biophys Acta. 1979;571:305–12.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, 26506, Morgantown, WV, USA

    Jia Luo

Authors
  1. Jia Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jia Luo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, J. The role of matrix metalloproteinases in the morphogenesis of the cerebellar cortex. Cerebellum 4, 239–245 (2005). https://doi.org/10.1080/14734220500247646

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1080/14734220500247646

Key words

Search

Navigation