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Bone marrow derived macrophage response to CSF1R stimulation or starvation after deletion of Ptpn6 or Rraga

ABSTRACT: A genome-wide CRISPR screen in primary mouse bone marrow derived macrophages identified Rraga and Ptpn6 as important regulators of cell death upon CSF-1 starvation. To explore how Rraga and Ptpn6 deletion influence cellular state after CSF-1 stimulation or during growth factor starvation, CRISPR-edited BMDMs were harvested at different timepoints after addition of CSF-1, which is required to maintain cellular survival in these cultures. RNA-seq and differential expression analyses were conducted to illuminate differential pro-survival mechanisms in cultures lacking Ptpn6 or Rraga, respectively.

ORGANISM(S): Mus musculus

PROVIDER: GSE312715 | GEO | 2026/03/26

REPOSITORIES: GEO

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Project description:Deficiency in the protein-tyrosine phosphatase SHP1/PTPN6 is linked with hematological malignancies and chronic inflammatory diseases. Here we exploited the embryonic and larval stages of zebrafish as an animal model to study ptpn6 function in the sole context of innate immunity. We show that ptpn6 knockdown induces a spontaneous inflammation-associated phenotype at the late larval stage, which was microbe-independent and enhanced instead of suppressed by glucocorticoids. When challenged with Salmonella typhimurium or Mycobacterium marinum at earlier stages of development, the innate immune system was hyperactivated to a contra-productive level that impaired the control of these pathogenic bacteria. These results demonstrate the crucial regulatory function of ptpn6 in preventing host-detrimental effects of inflammation by imposing a tight control over the level of innate immune response activation. This microarray study was designed to determine the effect of morpholino knockdown of the ptpn6 gene on the innate immune response of zebrafish embryos during infection with Salmonella typhimurium. Three independent infection experiments were performed using mixed egg clutches of wild type zebrafish, which were a cross of the AB and TL strains. Each experiment consisted of the following four treatment groups: (1) uninfected control embryos, (2) S. typhimurium-infected control embryos, (3) uninfected ptpn6 knockdown embryos, and (4) S. typhimurium-infected ptpn6 knockdown embryos. Knockdown of ptpn6 was performed by micro-injecting embryos at the 1-2 cell stage with the ptpn6 morpholino, and control embryos were mock-injected with buffer. Embryos were grown at 28.5M-bM-^@M-^S30M-BM-0C in egg water and manually dechorionated at 24 hours post fertilization (hpf). Subsequently, embryos were infected at 28 hpf by micro-injecting 200-250 colony forming units (CFU) of S. typhimurium SL1027 bacteria into the caudal vein, or were mock-injected with buffer as a control. After injections embryos were transferred into fresh egg water and incubated for 8 h at 28M-BM-0C. After the incubation period, pools of 15-20 embryos per treatment group were snap-frozen in liquid nitrogen and RNA was isolated for microarray analysis. All treatment groups were analyzed using a common reference approach.

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Bone marrow derived macrophage response to CSF1R stimulation or starvation after deletion of Ptpn6 or Rraga

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