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. 2017 Mar 29;140(5):1447–1465. doi: 10.1093/brain/awx060

Figure 7.

Figure 7

Neuronal progranulin depletion with CaMKII-Cre and Nestin-Cre significantly reduces total brain progranulin.CaMKII-Cre N-KO mice exhibited significant reductions in progranulin RNA in the frontal cortex and amygdala (A, ANOVA effect of genotype, P = 0.0096). Progranulin protein levels were also reduced in the frontal cortex (FC) and amygdala (AMG) of CaMKII-Cre N-KO mice (B, ANOVA effect of genotype, P = 0.0189). Grn RNA and protein levels were not reduced in the thalamus of CaMKII-Cre N-KO mice, which is consistent with low CaMKII-Cre expression in this brain region. Progranulin immunostaining (C and D) was used to provide a semiquantitative screen of progranulin levels across the brain, and revealed progranulin depletion in the cortex (cingulate and insula), hippocampus (CA1 and CA3), and basolateral amygdala of CaMKII-Cre N-KO mice (repeated measures ANOVA effect of genotype P = 0.0039, genotype × region interaction P < 0.0001). Nestin-Cre N-KO mice exhibited even stronger reductions in total progranulin levels throughout the brain. Total progranulin RNA (E, repeated measures ANOVA effect of genotype, P < 0.0001) and protein (F, repeated measures ANOVA effect of genotype, P < 0.0001) were reduced in frontal cortex (FC), amygdala (AMG), and thalamus (Thal). Analysis of progranulin immunoreactivity (G) showed strong reduction of progranulin throughout the forebrain in Nestin-Cre N-KO mice (H, repeated measures ANOVA effect of genotype, P < 0.0001, genotype × brain region interaction, P < 0.0001). ELISA and quantitative PCR data were analysed by ANOVA, with one-tailed t-test used to compare progranulin levels between Cre+ N-KO mice and Cre− littermates within each brain region. Immunostaining data were analysed by repeated measures ANOVA, followed by Sidak’s post hoc test. n = 8–17 per genotype for ELISAs and 9–10 per group for immunostaining. *P < 0.05, **P < 0.01, ****P < 0.0001. ACc = nucleus accumbens core; ACs = nucleus accumbens shell; AMG = amygdala; ARC = arcuate nucleus; BLA = basolateral amygdala; CeA = central amygdala; Cg = cingulate cortex; DG = dentate gyrus; FC = frontal cortex; IC = insular cortex; MD = mediodorsal thalamic nucleus; MeA = medial amygdala; Thal = thalamus; VMH = ventromedial hypothalamus; VPM = ventral posteromedial thalamic nucleus.