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Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding

Nature Neuroscience volume 6, pages 1292–1299 (2003)Cite this article

Abstract

Lysophosphatidic acid (LPA) is a phospholipid that has extracellular signaling properties mediated by G protein–coupled receptors. Two LPA receptors, LPA1 and LPA2, are expressed in the embryonic cerebral cortex, suggesting roles for LPA signaling in cortical formation. Here we report that intact cerebral cortices exposed to extracellular LPA ex vivo rapidly increased in width and produced folds resembling gyri, which are not normally present in mouse brains and are absent in LPA1 LPA2 double-null mice. Mechanistically, growth was not due to increased proliferation but rather to receptor-dependent reduced cell death and increased terminal mitosis of neural progenitor cells (NPCs). Our results implicate extracellular lipid signals as new influences on brain formation during embryonic development.

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Figure 1: Ex vivo culture system simulates in vivo neurogenic parameters.
Figure 5: LPA promotes terminal mitosis, but not faster migration, of NPCs.
Figure 2: LPA induces cortical folds.
Figure 3: Cortical folds arise at later time points in culture.
Figure 4: LPA increases cortical thickness and cell number.
Figure 6: LPA decreases cell death.
Figure 7: LPA's effects are observed throughout the telencephalon.
Figure 8: Effects of LPA are absent in mice null for both LPA1 and LPA2.

References

  1. Rakic, P. A small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution. Trends Neurosci. 18, 383–388 (1995).

    Article  CAS  Google Scholar 

  2. Caviness, V.S. Jr., Takahashi, T. & Nowakowski, R.S. Numbers, time and neocortical neuronogenesis: a general developmental and evolutionary model. Trends Neurosci. 18, 379–383 (1995).

    Article  CAS  Google Scholar 

  3. Haydar, T.F., Kuan, C.Y., Flavell, R.A. & Rakic, P. The role of cell death in regulating the size and shape of the mammalian forebrain. Cereb. Cortex 9, 621–626 (1999).

    Article  CAS  Google Scholar 

  4. Pompeiano, M., Blaschke, A.J., Flavell, R.A., Srinivasan, A. & Chun, J. Decreased apoptosis in proliferative and postmitotic regions of the caspase 3–deficient embryonic central nervous system. J. Comp. Neurol. 423, 1–12 (2000).

    Article  CAS  Google Scholar 

  5. LoTurco, J.J., Owens, D.F., Heath, M.J., Davis, M.B. & Kriegstein, A.R. GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15, 1287–1298 (1995).

    Article  CAS  Google Scholar 

  6. Drago, J., Murphy, M., Carroll, S.M., Harvey, R.P. & Bartlett, P.F. Fibroblast growth factor–mediated proliferation of central nervous system precursors depends on endogenous production of insulin-like growth factor I. Proc. Natl. Acad. Sci. USA 88, 2199–2203 (1991).

    Article  CAS  Google Scholar 

  7. Ghosh, A. & Greenberg, M.E. Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis. Neuron 15, 89–103 (1995).

    Article  CAS  Google Scholar 

  8. Temple, S. & Qian, X. bFGF, neurotrophins and the control of cortical neurogenesis. Neuron 15, 249–252 (1995).

    Article  CAS  Google Scholar 

  9. Vaccarino, F.M. et al. Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis. Nat. Neurosci. 2, 246–253 (1999).

    Article  CAS  Google Scholar 

  10. Suh, J., Lu, N., Nicot, A., Tatsuno, I. & DiCicco-Bloom, E. PACAP is an anti-mitogenic signal in developing cerebral cortex. Nat. Neurosci. 4, 123–124 (2001).

    Article  CAS  Google Scholar 

  11. Fukushima, N., Ishii, I., Contos, J.J., Weiner, J.A. & Chun, J. Lysophospholipid receptors. Annu. Rev. Pharmacol. Toxicol. 41, 507–534 (2001).

    Article  CAS  Google Scholar 

  12. Chun, J. et al. International union of pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 54, 265–269 (2002).

    Article  CAS  Google Scholar 

  13. Contos, J.J. & Chun, J. The mouse lp A3 /Edg7 lysophosphatidic acid receptor gene: genomic structure, chromosomal localization, and expression pattern. Gene 267, 243–253 (2001).

    Article  CAS  Google Scholar 

  14. Hecht, J.H., Weiner, J.A., Post, S.R. & Chun, J. Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J. Cell. Biol. 135, 1071–1083 (1996).

    Article  CAS  Google Scholar 

  15. McGiffert, C., Contos, J.J., Friedman, B. & Chun, J. Embryonic brain expression analysis of lysophospholipid receptor genes suggests roles for s1p 1 in neurogenesis and s1p 1–3 in angiogenesis. FEBS Lett. 531, 103–108 (2002).

    Article  CAS  Google Scholar 

  16. Dubin, A.E., Bahnson, T., Weiner, J.A., Fukushima, N. & Chun, J. Lysophosphatidic acid stimulates neurotransmitter-like conductance changes that precede GABA and L-glutamate in early, presumptive cortical neuroblasts. J. Neurosci. 19, 1371–1381 (1999).

    Article  CAS  Google Scholar 

  17. Fukushima, N., Weiner, J.A. & Chun, J. Lysophosphatidic acid (LPA) is a novel extracellular regulator of cortical neuroblast morphology. Dev. Biol. 228, 6–18 (2000).

    Article  CAS  Google Scholar 

  18. Contos, J.J., Fukushima, N., Weiner, J.A., Kaushal, D. & Chun, J. Requirement for the lp A1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc. Natl. Acad. Sci. USA 97, 13384–13389 (2000).

    Article  CAS  Google Scholar 

  19. Contos, J.J. et al. Characterization of lpa 2 (Edg4) and lpa 1 /lpa 2 (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa 2 . Mol. Cell Biol. 22, 6921–6929 (2002).

    Article  CAS  Google Scholar 

  20. Sauer, F. Mitosis in the neural tube. J. Comp. Neurol. 62, 377–405 (1935).

    Article  Google Scholar 

  21. Sidman, R.L., Miale, I.L. & Feder, N. Cell proliferation and migration in the primitive ependymal zone: an autoradiographic study of histogenesis in the nervous system. Exp. Neurol. 1, 322–333 (1959).

    Article  CAS  Google Scholar 

  22. Hendzel, M.J. et al. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma 106, 348–360 (1997).

    Article  CAS  Google Scholar 

  23. Rehen, S.K. et al. Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc. Natl. Acad. Sci. USA 98, 13361–13366 (2001).

    Article  CAS  Google Scholar 

  24. Takahashi, T., Nowakowski, R.S. & Caviness, V.S. Jr. Cell cycle parameters and patterns of nuclear movement in the neocortical proliferative zone of the fetal mouse. J. Neurosci. 13, 820–833 (1993).

    Article  CAS  Google Scholar 

  25. Takahashi, T., Nowakowski, R.S. & Caviness, V.S., Jr. The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall. J. Neurosci. 15, 6046–6057 (1995).

    Article  CAS  Google Scholar 

  26. Cai, L., Hayes, N.L. & Nowakowski, R.S. Local homogeneity of cell cycle length in developing mouse cortex. J. Neurosci. 17, 2079–2087 (1997).

    Article  CAS  Google Scholar 

  27. Moolenaar, W.H. Lysophosphatidic acid signalling. Curr. Opin. Cell Biol. 7, 203–210 (1995).

    Article  CAS  Google Scholar 

  28. Menezes, J.R. & Luskin, M.B. Expression of neuron-specific tubulin defines a novel population in the proliferative layers of the developing telencephalon. J. Neurosci. 14, 5399–5416 (1994).

    Article  CAS  Google Scholar 

  29. Ye, X., Ishii, I., Kingsbury, M.A. & Chun, J. Lysophosphatidic acid as a novel cell survival/apoptotic factor. Biochim. Biophys. Acta. 1585, 108–113 (2002).

    Article  CAS  Google Scholar 

  30. Blaschke, A.J., Staley, K. & Chun, J. Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex. Development 122, 1165–1174 (1996).

    CAS  PubMed  Google Scholar 

  31. Blaschke, A.J., Weiner, J.A. & Chun, J. Programmed cell death is a universal feature of embryonic and postnatal neuroproliferative regions throughout the central nervous system. J. Comp. Neurol. 396, 39–50 (1998).

    Article  CAS  Google Scholar 

  32. Ishii, I., Contos, J.J., Fukushima, N. & Chun, J. Functional comparisons of the lysophosphatidic acid receptors, LPA1/VZG-1/EDG-2, LPA2/EDG-4, and LPA3/EDG-7 in neuronal cell lines using a retrovirus expression system. Mol. Pharmacol. 58, 895–902 (2000).

    Article  CAS  Google Scholar 

  33. Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).

    Article  CAS  Google Scholar 

  34. Chenn, A. & Walsh, C.A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002).

    Article  CAS  Google Scholar 

  35. Ishii, I., Fukushima, N., Ye, X. & Chun, J. Lysophospholipid receptors: signaling and biology. Annu. Rev. Biochem. (in press).

  36. Fukushima, N. et al. Lysophosphatidic acid influences the morphology and motility of young, postmitotic cortical neurons. Mol. Cell Neurosci. 20, 271–282 (2002).

    Article  CAS  Google Scholar 

  37. Jalink, K., Eichholtz, T., Postma, F.R., van Corven, E.J. & Moolenaar, W.H. Lysophosphatidic acid induces neuronal shape changes via a novel, receptor-mediated signaling pathway: similarity to thrombin action. Cell Growth Differ. 4, 247–255 (1993).

    CAS  PubMed  Google Scholar 

  38. Umezu-Goto, M. et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J. Cell. Biol. 158, 227–233 (2002).

    Article  CAS  Google Scholar 

  39. Tokumura, A. et al. Identification of human plasma lysophospholipase D, a lysophosphatidic acid–producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J. Biol. Chem. 277, 39436–39442 (2002).

    Article  CAS  Google Scholar 

  40. Brauer, A.U. et al. A new phospholipid phosphatase, PRG-1, is involved in axon growth and regenerative sprouting. Nat. Neurosci. 6, 572–578 (2003).

    Article  Google Scholar 

  41. Thomaidou, D., Mione, M.C., Cavanagh, J.F. & Parnavelas, J.G. Apoptosis and its relation to the cell cycle in the developing cerebral cortex. J. Neurosci. 17, 1075–1085 (1997).

    Article  CAS  Google Scholar 

  42. Le Gros Clark, W.E. Deformation patterns on the cerebral cortex. in Essays on Growth and Form (eds. Le Gros Clark, W.E. & Medawar, P.B.) 1–22 (Oxford Univ. Press, London, 1945).

    Google Scholar 

  43. Richman, D.P., Stewart, R.M., Hutchinson, J.W. & Caviness, V.S. Jr. Mechanical model of brain convolutional development. Science 189, 18–21 (1975).

    Article  CAS  Google Scholar 

  44. Barron, D.H. An experimental analysis of some factors involved in the development of fissure pattern of the cerebral cortex. J. Exp. Zool. 113, 553–573 (1950).

    Article  Google Scholar 

  45. Gage, F.H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

    Article  CAS  Google Scholar 

  46. Alvarez-Buylla, A., Garcia-Verdugo, J.M. & Tramontin, A.D. A unified hypothesis on the lineage of neural stem cells. Nat. Rev. Neurosci. 2, 287–293 (2001).

    Article  CAS  Google Scholar 

  47. Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).

    Article  CAS  Google Scholar 

  48. Fukushima, N., Kimura, Y. & Chun, J. A single receptor encoded by vzg-1/lp A1/edg-2 couples to G proteins and mediates multiple cellular responses to lysophosphatidic acid. Proc. Natl. Acad. Sci. USA 95, 6151–6156 (1998).

    Article  CAS  Google Scholar 

  49. Takahashi, T., Nowakowski, R.S. & Caviness, V.S., Jr. Interkinetic and migratory behavior of a cohort of neocortical neurons arising in the early embryonic murine cerebral wall. J. Neurosci. 16, 5762–5776 (1996).

    Article  CAS  Google Scholar 

  50. Rehen, S.K., Cid, M., Fragel-Madeira, L. & Linden, R. Differential effects of cyclin-dependent kinase blockers upon cell death in the developing retina. Brain Res. 947, 78–83 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank B. Friedman, D. Kaushal, M. McConnell, A. Yang, X. Ye and J. H. Brown for useful discussions regarding this work; B. Almeida, M. Fontanoz, J. Goodson and G. Kennedy for technical assistance; J. Goodson for critical reading of this manuscript; and H. Karten for assistance with photography. This work was supported by the National Institute of Mental Health and Human Frontiers Science Program (J.C.), a Neuroplasticity of Aging Training Grant postdoctoral fellowship from the National Institute of Aging (M.A.K.), a postdoctoral fellowship from the PEW Latin American Fellows in the Biomedical Sciences (S.K.R.), a predoctoral fellowship from the Howard Hughes Medical Institute and a Merck fellow award (C.M.H.) and The Helen L. Dorris Institute for the Study of Neurological and Psychiatric Disorders of Children and Adolescents (J.C., M.A.K., S.K.R., C.M.H.).

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Author notes

  1. Marcy A Kingsbury and Stevens K Rehen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND 118, La Jolla, 92037, California, USA

    Marcy A Kingsbury, Stevens K Rehen, Christine M Higgins & Jerold Chun

  2. Department of Pharmacology, The University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Marcy A Kingsbury, Stevens K Rehen, James J A Contos & Jerold Chun

  3. Neuroscience Program, The University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Christine M Higgins

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Correspondence to Jerold Chun.

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Kingsbury, M., Rehen, S., Contos, J. et al. Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nat Neurosci 6, 1292–1299 (2003). https://doi.org/10.1038/nn1157

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