title: Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth.
abstract: Whereas carcinogenesis requires the acquisition of driver mutations in progenitor cells, tumor growth and progression are heavily influenced by the local microenvironment. Previous studies from our laboratory have used Neurofibromatosis-1 (NF1) genetically engineered mice to characterize the role of stromal cells and signals to optic glioma formation and growth. Previously, we have shown that Nf1+/- microglia in the tumor microenvironment are critical cellular determinants of optic glioma proliferation. To define the role of microglia in tumor formation and maintenance further, we used CD11b-TK mice, in which resident brain microglia (CD11b+, CD68+, Iba1+, CD45low cells) can be ablated at specific times after ganciclovir administration. Ganciclovir-mediated microglia reduction reduced Nf1 optic glioma proliferation during both tumor maintenance and tumor development. We identified the developmental window during which microglia are increased in the Nf1+/- optic nerve and demonstrated that this accumulation reflected delayed microglia dispersion. The increase in microglia in the Nf1+/- optic nerve was associated with reduced expression of the chemokine receptor, CX3CR1, such that reduced Cx3cr1 expression in Cx3cr1-GFP heterozygous knockout mice led to a similar increase in optic nerve microglia. These results establish a critical role for microglia in the development and maintenance of Nf1 optic glioma.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Simmons
authors.forename: Winnie W
authors.initials: WW
authors.lastname: Pong
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Emnett
authors.forename: Crystal R
authors.initials: CR
authors.lastname: White
authors.forename: Scott M
authors.initials: SM
authors.lastname: Gianino
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000818:Animals; D018845:CD11 Antigens / Q000235:genetics; D000073883:CX3C Chemokine Receptor 1; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D006580:Genetic Carrier Screening; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000235:genetics*; D020339:Optic Nerve Glioma / Q000235:genetics* / Q000473:pathology*; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D018845:CD11 Antigens; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine