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

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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.


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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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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) doi:10.1038/nn1157

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