Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth

Grant W. Simmons, Winnie W. Pong, Ryan J. Emnett, Crystal R. White, Scott M. Gianino, Fausto J. Rodriguez, David H. Gutmann

Research output: Contribution to journalArticle

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 cellulardeterminants 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 similarincrease in optic nerve microglia. These results establish a critical role for microglia in the development and maintenance ofNf1 optic glioma.

Original languageEnglish (US)
Pages (from-to)51-62
Number of pages12
JournalJournal of neuropathology and experimental neurology
Volume70
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Keywords

  • Astrocytoma
  • Chemokine
  • Fractalkine receptor
  • Microenvironment
  • Optic glioma
  • Stroma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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