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

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.