Region-specific astrogliosis in brains of mice heterozygous for mutations in the neurofibromatosis type 1 (Nf1) tumor suppressor

Abstract

Brains from human neurofibromatosis type 1 (NF1) patients show increased expression of glial fibrillary acidic protein (GFAP), consistent with activation of astrocytes (M.L. Nordlund, T.A. Rizvi, C.I. Brannan, N. Ratner, Neurofibromin expression and astrogliosis in neurofibromatosis (type 1) brains, J. Neuropathol. Exp. Neurology 54 (1995) 588-600). We analyzed brains from transgenic mice in which the Nf1 gene was targeted by homologous recombination. We show here that, in all heterozygous mice analyzed, there are increased numbers of astrocytes expressing high levels of GFAP in medial regions of the periaqueductal gray and in the nucleus accumbens. More subtle, but significant, changes in the number of GFAP positive astrocytes were observed in the hippocampus in 60% of mutant mice analyzed. Astrocytes with elevated GFAP were present at 1 month, 2 months, 6 months and 12 months after birth. Most brain regions, including the cerebellum, basal ganglia, cerebral cortex, hypothalamus, thalamus, cortical amygdaloid area, and white matter tracts did not show any gliotic changes. No evidence of degenerating neurons was found using de Olmos' cupric silver stain. We conclude that Nf1/nf1 mice provide a model to study astrogliosis associated with neurofibromatosis type 1.

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

“…In this report, we demonstrate that Nf1+/7 mice demonstrate increased numbers of GFAP-immunoreactive astrocytes in the brain, similar to that described for individuals a ected with NF1. Recently, Ratner and colleagues have reported similar increases in GFAP-immunoreactivity in brains from mice heterozygous for a targeted Nf1 mutation, con®rming the observations reported herein (Rizvi et al, 1999). We further demonstrate that this increase in GFAP-immunoreactive astrocytes re¯ects increased astrocyte proliferation both in vitro and in vivo.…”

“…The lack of increased astrocyte proliferation in vitro raised the possibility that the observed increases in GFAP-immunoreactive astrocytes in the brain re¯ected reactive astrogliosis and not increased proliferation (Rizvi et al, 1999). Alternatively, it is possible that reduced Nf1 expression does not confer a cell autonomous growth advantage, but rather an abnormal response to other stimuli.…”

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

“…Astrogliosis is an indicator for neuronal injury or toxicity, but not necessarily associated with neuronal cell death. 18 Therefore, the gliosis we have observed in Sp4 mutant mice may result from astrocytic or neuronal abnormalities, but in either case is likely to reflect subtle changes in cells, rather than cell death. Considering that Sp4 is specifically expressed in neurons, and not in glial cells, it is likely that the astrogliosis is a secondary effect generated by the malfunction of the hippocampal neurons.…”

Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells

“…Vimentin is an intermediate ®lament protein expressed in immature and reactive astrocytes (Eddleston and Mucke, 1993;Lendahl et al, 1990), while ApoE upregulation correlates with astrogliosis (Mouchel et al, 1995). No increased expression of vimentin, ApoE, or GFAP was observed in brains from Tsc2+/7 mice compared with wild type mice (Figure 3), suggesting that the increase in the number of GFAP-immunoreactive astrocytes was not a result of reactive astrogliosis (Rizvi et al, 1999), but rather increased astrocyte number.…”