Molecular Neurobiology

, Volume 45, Issue 1, pp 17–29 | Cite as

An Aberrant Cerebellar Development in Mice Lacking Matrix Metalloproteinase-3

  • Inge Van Hove
  • Mieke Verslegers
  • Tom Buyens
  • Nathalie Delorme
  • Kim Lemmens
  • Stijn Stroobants
  • Ilse Gantois
  • Rudi D’Hooge
  • Lieve Moons


Cell–cell and cell–matrix interactions are necessary for neuronal patterning and brain wiring during development. Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of remodelling the pericellular environment and regulating signaling pathways through cleavage of a large degradome. MMPs have been suggested to affect cerebellar development, but the specific role of different MMPs in cerebellar morphogenesis remains unclear. Here, we report a role for MMP-3 in the histogenesis of the mouse cerebellar cortex. MMP-3 expression peaks during the second week of postnatal cerebellar development and is most prominently observed in Purkinje cells (PCs). In MMP-3 deficient (MMP-3−/−) mice, a protracted granule cell (GC) tangential migration and a delayed GC radial migration results in a thicker and persistent external granular layer, a retarded arrival of GCs in the inner granular layer, and a delayed GABAergic interneuron migration. Importantly, these neuronal migration anomalies, as well as the consequent disturbed synaptogenesis on PCs, seem to be caused by an abnormal PC dendritogenesis, which results in reduced PC dendritic trees in the adult cerebellum. Of note, these developmental and adult cerebellar defects might contribute to the aberrant motor phenotype observed in MMP-3−/− mice and suggest an involvement of MMP-3 in mouse cerebellar development.


Matrix metalloproteinase-3 Development Cerebellum Neuronal patterning Purkinje cell dendritogenesis Neuronal wiring 


  1. 1.
    Hatten ME (1999) Central nervous system neuronal migration. Annu Rev Neurosci 22:511–539PubMedCrossRefGoogle Scholar
  2. 2.
    Sotelo C (2004) Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol 72:295–339PubMedCrossRefGoogle Scholar
  3. 3.
    Takayama C, Inoue Y (2004) GABAergic signaling in the developing cerebellum. Anat Sci Int 79:124–136PubMedCrossRefGoogle Scholar
  4. 4.
    Rivera S, Khrestchatisky M, Kaczmarek L, Rosenberg GA, Jaworski DM (2010) Metzincin proteases and their inhibitors: foes or friends in nervous system physiology? J Neurosci 30:15337–15357PubMedCrossRefGoogle Scholar
  5. 5.
    Vaillant C, Didier-Bazes M, Hutter A, Belin MF, Thomasset N (1999) Spatiotemporal expression patterns of metalloproteinases and their inhibitors in the postnatal developing rat cerebellum. J Neurosci 19:4994–5004PubMedGoogle Scholar
  6. 6.
    Ayoub AE, Cai TQ, Kaplan RA, Luo J (2005) Developmental expression of matrix metalloproteinases 2 and 9 and their potential role in the histogenesis of the cerebellar cortex. J Comp Neurol 481:403–415PubMedCrossRefGoogle Scholar
  7. 7.
    Vaillant C, Meissirel C, Mutin M, Belin MF, Lund LR, Thomasset N (2003) MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum. Mol Cell Neurosci 24:395–408PubMedCrossRefGoogle Scholar
  8. 8.
    Ngimbous BB, Bourgeois F, Mas C, Simonneau M, Moalic JM (2001) Heart transplantation changes the expression of distinct gene families. Physiol Genomics 7:115–126PubMedGoogle Scholar
  9. 9.
    Ulrich R, Gerhauser I, Seeliger F, Baumgartner W, Alldinger S (2005) Matrix metalloproteinases and their inhibitors in the developing mouse brain and spinal cord: a reverse transcription quantitative polymerase chain reaction study. Dev Neurosci 27:408–418PubMedCrossRefGoogle Scholar
  10. 10.
    Schefe JH, Lehmann KE, Buschmann IR, Unger T, Funke-Kaiser H (2006) Quantitative real-time RT-PCR data analysis: current concepts and the novel “gene expression’s CT difference” formula. J Mol Med 84:901–910PubMedCrossRefGoogle Scholar
  11. 11.
    Goddyn H, Leo S, Meert T, D’Hooge R (2006) Differences in behavioural test battery performance between mice with hippocampal and cerebellar lesions. Behav Brain Res 173:138–147PubMedCrossRefGoogle Scholar
  12. 12.
    Jaworski DM, Soloway P, Caterina J, Falls WA (2006) Tissue inhibitor of metalloproteinase-2(TIMP-2)-deficient mice display motor deficits. J Neurobiol 66:82–94PubMedCrossRefGoogle Scholar
  13. 13.
    Hager G, Dodt HU, Zieglgansberger W, Liesi P (1995) Novel forms of neuronal migration in the rat cerebellum. J Neurosci Res 40:207–219PubMedCrossRefGoogle Scholar
  14. 14.
    Yamamoto M, Boyer AM, Crandall JE, Edwards M, Tanaka H (1986) Distribution of stage-specific neurite-associated proteins in the developing murine nervous system recognized by a monoclonal antibody. J Neurosci 6:3576–3594PubMedGoogle Scholar
  15. 15.
    Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512PubMedCrossRefGoogle Scholar
  16. 16.
    Kawaji K, Umeshima H, Eiraku M, Hirano T, Kengaku M (2004) Dual phases of migration of cerebellar granule cells guided by axonal and dendritic leading processes. Mol Cell Neurosci 25:228–240PubMedCrossRefGoogle Scholar
  17. 17.
    Komuro H, Rakic P (1998) Distinct modes of neuronal migration in different domains of developing cerebellar cortex. J Neurosci 18:1478–1490Google Scholar
  18. 18.
    Lin JC, Cepko CL (1998) Granule cell raphes and parasagittal domains of Purkinje cells: complementary patterns in the developing chick cerebellum. J Neurosci 18:9342–9353Google Scholar
  19. 19.
    Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by sonic hedgehog. Neuron 22:103–114PubMedCrossRefGoogle Scholar
  20. 20.
    Guan CB, Xu HT, Jin M, Yuan XB, Poo MM (2007) Long-range Ca2+ signaling from growth cone to soma mediates reversal of neuronal migration induced by slit-2. Cell 129:385–395Google Scholar
  21. 21.
    Adcock KH, Metzger F, Kapfhammer JP (2004) Purkinje cell dendritic tree development in the absence of excitatory neurotransmission and of brain-derived neurotrophic factor in organotypic slice cultures. Neuroscience 127:137–145PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang L, Yokoi F, Jin YH, DeAndrade MP, Hashimoto K, Standaert DG, Li Y (2011) Altered dendritic morphology of Purkinje cells in Dyt1 DeltaGAG knock-in and Purkinje cell-specific Dyt1 conditional knockout mice. PLoS One 6:e18357PubMedCrossRefGoogle Scholar
  23. 23.
    McKay BE, Turner RW (2005) Physiological and morphological development of the rat cerebellar Purkinje cell. J Physiol 567:829–850PubMedCrossRefGoogle Scholar
  24. 24.
    Miyazaki T, Fukaya M, Shimizu H, Watanabe M (2003) Subtype switching of vesicular glutamate transporters at parallel fibre–Purkinje cell synapses in developing mouse cerebellum. Eur J Neurosci 17:2563–2572PubMedCrossRefGoogle Scholar
  25. 25.
    Leto K, Carletti B, Williams IM, Magrassi L, Rossi F (2006) Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci 26:11682–11694PubMedCrossRefGoogle Scholar
  26. 26.
    Fujita S (1967) Quantitative analysis of cell proliferation and differentiation in the cortex of the postnatal mouse cerebellum. J Cell Biol 32:277–287PubMedCrossRefGoogle Scholar
  27. 27.
    Morton SM, Bastian AJ (2004) Cerebellar control of balance and locomotion. Neuroscientist 10:247–259PubMedCrossRefGoogle Scholar
  28. 28.
    Rosenberg GA (2002) Matrix metalloproteinases in neuroinflammation. Glia 39:279–291PubMedCrossRefGoogle Scholar
  29. 29.
    Cauwe B, Opdenakker G (2010) Intracellular substrate cleavage: a novel dimension in the biochemistry, biology and pathology of matrix metalloproteinases. Crit Rev Biochem Mol Biol 45:351–423PubMedCrossRefGoogle Scholar
  30. 30.
    Si-Tayeb K, Monvoisin A, Mazzocco C et al. (2006) Matrix metalloproteinase 3 is present in the cell nucleus and is involved in apoptosis. Am J Pathol 169:1390–1401Google Scholar
  31. 31.
    Wetzel M, Li L, Harms KM, Roitbak T, Ventura PB, Rosenberg GA, Khokha R, Cunningham LA (2008) Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia. Cell Death Differ 15:143–151Google Scholar
  32. 32.
    Choi DH, Kim EM, Son HJ, Joh TH, Kim YS, Kim D, Flint Beal M, Hwang O (2008) A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells. J Neurochem 106:405–415Google Scholar
  33. 33.
    Tanaka M (2009) Dendrite formation of cerebellar Purkinje cells. Neurochem Res 34:2078–2088PubMedCrossRefGoogle Scholar
  34. 34.
    Feddersen RM, Ehlenfeldt R, Yunis WS, Clark HB, Orr HT (1992) Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice. Neuron 9:955–966PubMedCrossRefGoogle Scholar
  35. 35.
    Ruiz de Almodovar C, Coulon C, Salin PA, Knevels E, Chounlamountri N, Poesen K, Hermans K, Lambrechts D, Van Geyte K, Dhondt J, Dresselaers T, Renaud J, Aragones J, Zacchigna S, Geudens I, Gall D, Stroobants S, Mutin M, Dassonville K, Storkebaum E, Jordan BF, Eriksson U, Moons L, D’Hooge R, Haigh JJ, Belin MF, Schiffmann S, Van Hecke P, Gallez B, Vinckier S, Chedotal A, Honnorat J, Thomasset N, Carmeliet P, Meissirel C (2010) Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule cell migration in the cerebellum via VEGF receptor Flk1. J Neurosci 30:15052–15066PubMedCrossRefGoogle Scholar
  36. 36.
    Liesi P, Akinshola E, Matsuba K, Lange K, Morest K (2003) Cellular migration in the postnatal rat cerebellar cortex: confocal-infrared microscopy and the rapid Golgi method. J Neurosci Res 72:290–302PubMedCrossRefGoogle Scholar
  37. 37.
    Imai K, Kusakabe M, Sakakura T, Nakanishi I, Okada Y (1994) Susceptibility of tenascin to degradation by matrix metalloproteinases and serine proteinases. FEBS Lett 352:216–218PubMedCrossRefGoogle Scholar
  38. 38.
    Komuro H, Yacubova E (2003) Recent advances in cerebellar granule cell migration. Cell Mol Life Sci 60:1084–1098PubMedGoogle Scholar
  39. 39.
    McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I, Overall CM (2001) Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 276:43503–43508PubMedCrossRefGoogle Scholar
  40. 40.
    Borghesani PR, Peyrin JM, Klein R, Rubin J, Carter AR, Schwartz PM, Luster A, Corfas G, Segal RA (2002) BDNF stimulates migration of cerebellar granule cells. Development 129:1435–1442PubMedGoogle Scholar
  41. 41.
    Hisatsune C, Kuroda Y, Akagi T, Torashima T, Hirai H, Hashikawa T, Inoue T, Mikoshiba K (2006) Inositol 1,4,5-trisphosphate receptor type 1 in granule cells, not in Purkinje cells, regulates the dendritic morphology of Purkinje cells through brain-derived neurotrophic factor production. J Neurosci 26:10916–10924PubMedCrossRefGoogle Scholar
  42. 42.
    Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948PubMedCrossRefGoogle Scholar
  43. 43.
    Schwartz PM, Borghesani PR, Levy RL, Pomeroy SL, Segal RA (1997) Abnormal cerebellar development and foliation in BDNF−/− mice reveals a role for neurotrophins in CNS patterning. Neuron 19:269–281PubMedCrossRefGoogle Scholar
  44. 44.
    Xu ZQ, Sun Y, Li HY, Lim Y, Zhong JH, Zhou XF (2011) Endogenous proBDNF is a negative regulator of migration of cerebellar granule cells in neonatal mice. Eur J Neurosci 33:1376–1384PubMedCrossRefGoogle Scholar
  45. 45.
    Hahn-Dantona E, Ramos-DeSimone N, Sipley J, Nagase H, French DL, Quigley JP (1999) Activation of proMMP-9 by a plasmin/MMP-3 cascade in a tumor cell model regulation by tissue inhibitors of metalloproteinases. Ann N Y Acad Sci 878:372–387PubMedCrossRefGoogle Scholar
  46. 46.
    Imai K, Shikata H, Okada Y (1995) Degradation of vitronectin by matrix metalloproteinases-1, -2, -3, -7 and -9. FEBS Lett 369:249–251PubMedCrossRefGoogle Scholar
  47. 47.
    Pauly T, Ratliff M, Pietrowski E, Neugebauer R, Schlicksupp A, Kirsch J, Kuhse J (2008) Activity-dependent shedding of the NMDA receptor glycine binding site by matrix metalloproteinase 3: a PUTATIVE mechanism of postsynaptic plasticity. PLoS One 3:e2681PubMedCrossRefGoogle Scholar
  48. 48.
    Takamori S (2006) VGLUTs: ‘exciting’ times for glutamatergic research? Neurosci Res 55:343–351PubMedCrossRefGoogle Scholar
  49. 49.
    Guijarro P, Simo S, Pascual M, Abasolo I, Del Rio JA, Soriano E (2006) Netrin1 exerts a chemorepulsive effect on migrating cerebellar interneurons in a Dcc-independent way. Mol Cell Neurosci 33:389–400PubMedCrossRefGoogle Scholar
  50. 50.
    Leto K, Bartolini A, Rossi F (2008) Development of cerebellar GABAergic interneurons: origin and shaping of the “minibrain” local connections. Cerebellum 7:523–529PubMedCrossRefGoogle Scholar
  51. 51.
    Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA, Luster AD (2001) SDF-1 alpha induces chemotaxis and enhances sonic hedgehog-induced proliferation of cerebellar granule cells. Development 128:1971–1981PubMedGoogle Scholar
  52. 52.
    Meng H, Larson SK, Gao R, Qiao X (2007) BDNF transgene improves ataxic and motor behaviors in stargazer mice. Brain Res 1160:47–57PubMedCrossRefGoogle Scholar
  53. 53.
    Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H, Sausbier U, Sailer CA, Feil R, Hofmann F, Korth M, Shipston MJ, Knaus HG, Wolfer DP, Pedroarena CM, Storm JF, Ruth P (2004) Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proc Natl Acad Sci USA 101:9474–9478PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Inge Van Hove
    • 1
  • Mieke Verslegers
    • 1
  • Tom Buyens
    • 1
  • Nathalie Delorme
    • 1
  • Kim Lemmens
    • 1
  • Stijn Stroobants
    • 2
  • Ilse Gantois
    • 2
  • Rudi D’Hooge
    • 2
  • Lieve Moons
    • 1
  1. 1.Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of BiologyK.U.LeuvenLeuvenBelgium
  2. 2.Laboratory of Biological Psychology, Department of PsychologyK.U.LeuvenLeuvenBelgium

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