The role of FGF signaling in suppressing astrogliosis

DESCRIPTION (provided by applicant): Gliosis is a response to brain damage and is a prominent feature of many neurological disorders including epilepsy, neurodegeneration, tumor growth, stroke, and trauma. The response to damage involves cell types from within the CNS and can include infiltrating immune cells. The extent of the response varies and is modulated by a number of secreted factors (Sofroniew, 2009; Kang and Hibert, 2011). For some of these factors, however, their requirement and role in gliosis has not been clearly defined or demonstrated in vivo. This is particularly true for Fibroblast Growth Factors (FGFs). Previous immunohistochemical analyses suggested that nuclear FGF2 and at least one receptor are up-regulated in astrocytes in response to damage (Eddleston and Mucke, 1993; Ridet et al., 1997). However, the significance of these immunostains is unknown. Moreover the role of FGF signaling in mature astrocytes in vivo under normal conditions as well as after injury remains unaddressed. The goal of this proposal is to provide definitive evidence for the role of FGFs in astrogliosis under normal conditions and in response to damage. To address the function of FGF signaling in the adult cerebrum, we conditionally deleted floxed alleles of Fgfr1 and Fgfr2 in an Fgfr3 null background. We used a NestinCreER mouse line in which CreER, upon tamoxifen treatment, is unexpectedly active specifically in astrocytes throughout the hippocampal and cortical parenchyma (in addition to the expected neurogenic regions). Our preliminary data indicate that in FGF receptor triple mutants there is a tremendous increase in astrocytic GFAP, Vimentin, and Nestin expression, indicative of astrogliosis. This increase in intermediate filaments is not observed in tamoxifen-treated heterozygous littermate controls that carry NestinCreER or in mutants that lack only one or two receptors. The absence of the phenotype in single and double mutants suggests functional compensation between receptors and may explain why this phenotype has not previously been reported. The increase in gliotic markers in the triple mutant is not accompanied by detectable signs of tissue damage, cell death, or obvious changes in the neurogenic regions. Moreover, our preliminary data suggests that the astrocytes that are reactive in the mutants are the ones that have lost FGF signaling whereas neighboring non-reactive ones have maintained signaling. This leads us to the hypothesis that FGF receptors act cell autonomously in the absence of injury to suppress astrogliosis.