title: Meningeal cells influence midbrain development and the engraftment of dopamine progenitors in Parkinsonian mice.
abstract: Dopaminergic neuroblasts, isolated from ventral midbrain fetal tissue, have been shown to structurally and functionally integrate, and alleviate Parkinsonian symptoms following transplantation. The use of donor tissue isolated at an age younger than conventionally employed can result in larger grafts - a consequence of improved cell survival and neuroblast proliferation at the time of implantation. However studies have paid little attention to removal of the meninges from younger tissue, due to its age-dependent tight attachment to the underlying brain. Beyond the protection of the central nervous system, the meninges act as a signaling center, secreting a variety of trophins to influence neural development and additionally impact on neural repair. However it remains to be elucidated what influence these cells have on ventral midbrain development and grafted dopaminergic neuroblasts. Here we examined the temporal role of meningeal cells in graft integration in Parkinsonian mice and, using in vitro approaches, identified the mechanisms underlying the roles of meningeal cells in midbrain development. We demonstrate that young (embryonic day 10), but not older (E12), meningeal cells promote dopaminergic differentiation as well as neurite growth and guidance within grafts and during development. Furthermore we identify stromal derived factor 1 (SDF1), secreted by the meninges and acting on the CXCR4 receptor present on dopaminergic progenitors, as a contributory mediator in these effects. These findings identify new and important roles for the meningeal cells, and SDF1/CXCR4 signaling, in ventral midbrain development as well as neural repair following cell transplantation into the Parkinsonian brain.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Fahad A
authors.initials: FA
authors.lastname: Somaa
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Bye
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Lachlan H
authors.initials: LH
authors.lastname: Thompson
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: cparish@unimelb.edu.au.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Parish
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001596:Benzylamines; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D000080027:Cyclams; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000502:physiology; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008578:Meninges / Q000166:cytology*; D008636:Mesencephalon / Q000166:cytology / Q000254:growth & development*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000601:surgery*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods*; D014404:Tubulin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D014404:Tubulin; C462941:beta3 tubulin, mouse; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; C088327:plerixafor; D004298:Dopamine
keywords: Axon growth; CXCR4; Chemokines; Dopamine development; Meninges; Parkinson's disease; SDF1; Transplantation