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Neuron-Specific Ablation of PDGF-B Is Compatible with Normal Central Nervous System Development and Astroglial Response to Injury

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Abstract

Members of the PDGF family have multiple roles during embryogenesis and in a variety of pathological situations in the adult. One of the major sites of PDGF-B expression in adult mammals are postmitotic CNS neurons. Combined with reported neurotrophic and neuroprotective effects of exogenously administered PDGFs, this has led to the speculation that PDGF-B may have a role in CNS development, in maintenance, or in response to CNS injury. To test these hypotheses, we developed mice in which PDGF-B was ablated genetically in postmitotic neurons at sites where PDGF-B is normally expressed. We found that these mice develop to adulthood without apparent defects. We demonstrate PDGF-B expression in the postnatal mouse hippocampus and forebrain cortex. We show that neuron-specific knockout of PDGF-B does not influence the astroglial and angiogenic responses to injury in the hippocampus or forebrain cortex. We conclude that the role of neuron-derived PDGF-B remains obscure. A role for neuron-derived PDGF-B, if existing, might be redundant with other CNS growth factors. Alternatively, other and more specific analyses of CNS functions in the normal and injured states will be required to demonstrate such a role.

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REFERENCES

  1. Heldin, C.-H., Eriksson, U., and östman, A. 2002. New members of the platelet-derived growth factor family of mitogens. Arch. Biochem. Biophys. 398:284–290.

    PubMed  Google Scholar 

  2. Heldin, C. H. and Westermark, B. 1999. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 79:1283–1316.

    PubMed  Google Scholar 

  3. Betsholtz, C., Karlsson, L., and Lindahl, P. 2001. Developmental roles of platelet-derived growth factors. BioEssays 23:494–507.

    PubMed  Google Scholar 

  4. Soriano, P. 1994. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev. 8:1888–1896.

    PubMed  Google Scholar 

  5. Levéen, P., Penkny, M., Gebre-Medhin, S., Swolin, B., Larsson, E., and Betsholtz, C. 1994. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 8:1875–1887.

    PubMed  Google Scholar 

  6. Lindahl, P., Johansson, B. R., Levéen, P., and Betsholtz, C. 1997. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245.

    PubMed  Google Scholar 

  7. Fruttiger, M., Karlsson, L., IIall, A. C., Abramsson, A., Calver, A. R., Boström, H., Willetts, K., Berthold, C.-H., Heath, J. K., Betsholtz, C. et. al. 1999. Defective oligodendrocyte development and severe hypomyelination in PDGF-A knockout mice. Development 126:457–467.

    PubMed  Google Scholar 

  8. Calver, A. R., Hall, A. C., Yu, W.,-P., Walsh, F. S., Heath, J. K., Betsholtz G., and Richardson, W. O. 1988. Oligodendrocyte population dynamics and the role of PDGF in vivo. Neuron. 20:869–882.

    Google Scholar 

  9. van Heyningen, P., Calver, A. R., and Richardson, W. R. 2001. Control of progenitor cell number by mitogen supply and demand. Curr. Biol. 11:232–241.

    PubMed  Google Scholar 

  10. Boström, H., Willetts, K., Pekny, M., Levéen, P., Lindahl, P., Hedstrand, H., Pekna, M., Hellström, M., Gebre-Medhin, S., Schalling, M. et. al. 1996. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85:863–873.

    PubMed  Google Scholar 

  11. Lindahl, P., Karlsson, L., Hellstrom, M., Gebre-Medhin, S., Willetts, K., Heath, J.K. and Betsholtz, C. 1997. Alveogenesis failure in PDGF-A deficient mice is coupled to lack distal spreading of alveolar smooth muscle cell progenitors during lung development. Development 124:3943–3953.

    PubMed  Google Scholar 

  12. Li, J. and Houyle, G. W. 2001. Overexpression of PDGF-A in the lung epithelium of transgenic mice produces a lethal phenotype associated with hyperplasia of mesenchymal cells. Dev. Biol. 239:338–349.

    PubMed  Google Scholar 

  13. Sasahara, M., Fries, J. W. U., Raines, E. W., Gown, A. M., Westrum, L. E., Frosch, M. P., Bonthron, D. T., Ross, R. and Collins, T. 1991. PDGF B-chain in neurons of the central nervous system, posterior pituitary and in a transgenic model. Cell 64:217–227.

    PubMed  Google Scholar 

  14. Sasahara, A., Kott, J. N., Sasahara, M., Raines, E. W., Ross, R. and Westrum, L. E. 1992. Platelet-derived growth factor B-chain-like immunoreactivity in the developing and adult rat brain. Dev. Brain Res. 68:41–53.

    Google Scholar 

  15. Smits, A., Kato, M., Westermark, B., Nistér, M., Heldin, C.-H. and Funa, K. 1991. Neurotrophic activity of platelet-derived growth factor (PDGF): Rat neuronal cells possess functional PDGF b-type receptors and respond to PDGF. Proc. Natl. Acad. Sci. USA, 88:8159–8163.

    PubMed  Google Scholar 

  16. Othberg, A., Odin, P., Ballagi, A., Åhgren, A., Funa, K. and Lindvall O. 1995. Specific effects of platelet-derived growth factor (PDGF) on fetal rat and human dopaminergic neurons in vivo. Exp. Brain Res. 105:111–122.

    PubMed  Google Scholar 

  17. Pietz, K., Odin, P., Funa, K. and Lindvall, O. 1996. Protective effect of platelet-derived growth factor against 6–hydroxydopamine-induced lesion of rat dopaminergic neurons in culture. Neurosci. Lett. 204:101–104.

    PubMed  Google Scholar 

  18. Funa, K., Yamada, N., Brodin, G., Pietz, K., Ähgren, A., Wictorin, K., Lindvall, O. and Odin, P. 1996. Enhanced synthesis of platelet-derived growth factor following injury induced by 6–hydroxydopamine in rat brains. Neuroscience 74:825–833.

    PubMed  Google Scholar 

  19. Hermanson, M., Olsson, T., Westermark, B. and Funa, K. 1995. PDGF and its receptors following facial nerve axotomy in rats: Expression in neurons and surrounding glia. Exp. Brain Res. 102:415–422.

    PubMed  Google Scholar 

  20. Heldin, C.-H., Westermark, B., and Wasteson, Å. 1981. Specific receptors for platelet-derived growth factor on cells derived from connective tissue and glia. Proc. Natl. Acad. Sci. USA 78:3664–3668.

    PubMed  Google Scholar 

  21. Nistér, M., Claesson-Welsh, L., Eriksson, A., Heldin, C.-H. and Westermark, B. 1991. Differential expression of platelet-derived growth factor receptors in human malignant glioma cell lines. J. Biol. Chem. 266:16755–16763.

    PubMed  Google Scholar 

  22. Fruttiger, M. 2002. Development of the mouse retinal vasculature: angiogenesis versus vasculogenesis. Invest. Ophtalmol. Vis. Sci. 43:522–527.

    Google Scholar 

  23. Heldin, C.-H., Wasteson, Å., and Westermark, B. 1980. Growth of normal human glial cells in a defined medium containing platelet-derived growth factor. Proc. Natl. Acad. Sci. USA 77:6611–6615.

    PubMed  Google Scholar 

  24. Enge, M., Bjarnegård, M., Gerhardt, H., Gustafsson, E., Kolén, M., Asker, N., Hammes, H.-P., Shani, M., Fässler, R. and Betsholtz, C. 2002. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. in press.

  25. Fan, G., Beard, C., Chen, R. Z., Csankovszki, G., Sun, Y., Siniaia, M., Biniszkiewicz, Bates, B., Lee, P. P., Kühn, R. et. al. 2001. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J. Neurosci. 21:788–797.

    PubMed  Google Scholar 

  26. Soriano, P. 1999. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21:70–71.

    PubMed  Google Scholar 

  27. Hogan, B., Beddington, R., Costantini, F. and Lacy, E. 1994. Manipulating the mouse embryo; a laboratory manual. 2nd ed. Cold Spring Harbor Laboratory Press.

  28. Hogan, B., Beddington, R., Costantini, F. and Lacy, E. 1999. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055.

    PubMed  Google Scholar 

  29. Karlsson, L., Bondjers, C., and Betsholtz, C. 1999. Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle. Development 126:2611–2621.

    PubMed  Google Scholar 

  30. Karlsson, L., Lindahl, P., Heath, J. K. and Betsholtz, C. 2000. Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development 127:3457–3466.

    PubMed  Google Scholar 

  31. Gnessi, L., Basciani, S., Mariani, S., Arizzi, M., Spera, G., Wang, C., Bondjers, C., Karlsson, L. and Betsholtz, C. 2000. Leydig cell loss and spermatogenic arrest in platelet-derived growth factor (PDGF)-A-deficient mice. J Cell Biol. 149:1019–1026.

    PubMed  Google Scholar 

  32. Shimokado, K., Raines, E. W., Madtes, D. K., Barrett, T. B., Benditt, E. P. and Ross, R. 1985. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 43:277–286.

    PubMed  Google Scholar 

  33. Martinet, Y., Bitterman, P. B., Mornex, J.-F., Grotendorst, G. R., Martin, G. R. and Crystal R. G. 1986. Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity. Nature. 319:158–160.

    PubMed  Google Scholar 

  34. Pekny, M., Johansson, C. B., Eliasson, C., Stakeberg, J., Wallén, Å., Perlmann, T., Lendahl U., Betsholtz, C., Berthold, C.-H. and Frisén, J. 1999. Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J. Cell Biol. 145:503–514.

    PubMed  Google Scholar 

  35. Eddleston, M. and Mucke, L. 1993. Molecular profile of reactive astrocytes: implications for their role in neurologic disease. Neuroscience 54:15–36.

    PubMed  Google Scholar 

  36. Eng, L. F. and Ghirnikar, R. S. 1994. GFAP and astrogliosis. Brain Pathol. 4:229–237.

    PubMed  Google Scholar 

  37. Gustafsson, E., Brakebusch, C., Hietanen, K. and Fassler R. 2001. Tie-l-directed expression of Cre recombinase in endothelial cells of embryoid bodies and transgenic mice. J. Cell Sci. 114:671–676.

    PubMed  Google Scholar 

  38. Abramsson, A., Berlin, Ö., Papayan, H., Paulin, D., Shani, M. and Betsholtz, C. 2002. Analysis of mural cell recruitment to tumor vessels. Circulation 105:112–117.

    PubMed  Google Scholar 

  39. Forsberg, K., Valyi, N. I., Heldin, C. H., Herlyn, M. and Westermark, B. 1993. Platelet-derived growth factor (PDGF) in oncogenesis: Development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc. Natl. Acad. Sci. USA 90:393–397.

    PubMed  Google Scholar 

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Enge, M., Wilhelmsson, U., Abramsson, A. et al. Neuron-Specific Ablation of PDGF-B Is Compatible with Normal Central Nervous System Development and Astroglial Response to Injury. Neurochem Res 28, 271–279 (2003). https://doi.org/10.1023/A:1022421001288

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  • DOI: https://doi.org/10.1023/A:1022421001288

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