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Transcriptomic profiling of mouse brain in PGRN KO, NesGrnOE-KOBG, EGFL7-PGRNdko and floxed control mice (Grnflfl)

ABSTRACT: Transcriptomic profiling of mouse brain in old progranulin deficient mice with a complete loss of progranulin (PGRN KO), with restoration of neuronal progranulin (NesGrnOE-KOBG), in progranulin-EGFL7 double deficient mice (EGFL7-PGRNdko) and floxed control mice (Grnflfl) Genetic progranulin deficiency in humans causes Frontotemporal Dementia (FTD). Progranulin knockout mice (PGRNko) are a model for the disease albeit cognitive impairment in mice is subtle. The predominant FTD-phenotype in mice are hyperactivity, sugar craving, compulsiveness, skin lesions owing to exessive grooming and general health issues in old mice such as anal prolaps. Progranulin in primarily expressed in neurons and in myeloid derived immune cells including microglia. Progranulin deficient microglia are neuron-aggressive and are believed to contribute to excessive synaptic pruning. It is not known if progranulin that is normally neurotrophic and keeps microglia in a neuron-supportive phenotype has to come from within microglia or is a progranulin-signal from neurons to microglia. To dissect out the differential contribution we generated mice which express progranulin in neurons via Nestin-driven restoration of progranulin expression in a progranulin knockout background. In addition we assessed additional deletion of EGFL7, which behaves as progranulin competitor for binding/activation of NOTCH receptors. Hence, this study describes and compared the transcriptome of old mice in four mouse lines: full progranulin knockout (PGRNko), neuronal resoration of PGRN on a knockout background (NesGrnOE-koBG), progranulin & EGFL7 double deletion (EGFL7-PGRNdko) and floxed progranulin control mice (Grn flfl). Mice were 60-70 weeks old at the the time of tissue collection. Total RNA was extracted with Qiagen RNAeasy micro-kits and sequencing librariers were prepared by Novogene according to standard protocols for mRNA sequencing. RNA seq was done on Illumina NovaSeq 6000. The sequence alignment was done with standard proceduers including quality filtering and adapter trimming with Qiagen's CLC Genomic Workbench. The TMM (trimmed mean od M-values) algorithm was used for read normalization. Total reads, RPKM and TPM are also provided in "Processed data" files.

ORGANISM(S): Mus musculus

PROVIDER: GSE273083 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Progranulin is a secreted pro-protein that is trafficked to lysosomes and exerts protective effects in the brain. Progranulin (GRN) mutations, most of which cause progranulin haploinsufficiency, are a major genetic cause of frontotemporal dementia (FTD). Restoring progranulin to people with GRN mutations is a promising treatment strategy, but understanding progranulin’s mechanism of action may enable design of optimal progranulin-based therapies. Progranulin restrains inflammation and promotes neuronal growth and survival, but the mechanisms underlying these effects are unclear. Progranulin is constitutively secreted and interacts with various signaling receptors, but is also taken up and trafficked to lysosomes, where it is necessary for maintaining normal lysosomal function. In previous work, we showed that progranulin acts in lysosomes to promote neuronal survival, but it is not clear if progranulin enhances neuronal growth by acting in lysosomes or through extracellular signaling. To address this question, we employed lentiviral vectors expressing either progranulin (PGRN) or a non-secreted, lysosome-targeted progranulin (L-PGRN). Using lentiviral vectors driven by non-selective (PGK), neuron-selective (hSyn), or astrocyte-selective (GFAP) promoters, we found that delivering L-PGRN to astrocytes, but not neurons, promoted dendritic outgrowth in primary hippocampal cultures. Using transwell co-cultures of astrocytes and neurons, we found that neurons cultured with L-PGRN–transduced astrocytes had greater dendritic outgrowth than those cultured with GFP-transduced astrocytes. Bulk RNA sequencing of primary astrocytes indicated that L-PGRN reduced transcriptomic pathways associated with inflammation and cellular reactivity. Consistent with this result, we found that reducing the number of astrocytes in hippocampal cultures increased dendritic outgrowth and occluded the pro-growth effects of L-PGRN. These data show that under these culture conditions, progranulin secretion is not required to promote dendritic outgrowth. Instead, progranulin may act via a non-cell–autonomous mechanism to suppress secretion of factors from astrocytes that restrain neuronal growth. These data add to a growing body of evidence that progranulin can act on astrocytes to promote neuronal health.

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Transcriptomic profiling of mouse brain in PGRN KO, NesGrnOE-KOBG, EGFL7-PGRNdko and floxed control mice (Grnflfl)

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