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Knockout of the selenocysteine tRNA (Trsp) gene in mouse macrophage

ABSTRACT: Comparative analysis of gene expression in bone marrow-derived macrophages (BMDM) from trsp knockout mice (Trspfl/fl-LysM-Cre+/-) and Control (Trspfl/fl-LysM-Cre-/-) mice. Selenium, a micronutrient whose deficiency in the diet causes immune dysfunction and inflammatory disorders, exerts its physiological effects partly in the form of selenium-containing proteins (selenoproteins). Incorporation of selenium into the amino acid selenocysteine (Sec), and subsequently into selenoproteins, is mediated by Sec tRNA[Ser]Sec. To identify macrophage-specific selenoprotein function, we generated mice with the Sec tRNA[Ser]Sec gene specifically deleted in myeloid cells. These mutant mice were devoid of the selenoproteome in macrophages, yet exhibited largely normal inflammatory responses. However, selenoprotein deficiency led to aberrant expression of extracellular matrix-related genes, and diminished migration of macrophages in a protein gel matrix. Therefore, selenium status may affect immune defense and tissue homeostasis through its effect on selenoprotein expression and the trafficking of tissue macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE15610 | GEO | 2009/12/22

SECONDARY ACCESSION(S): PRJNA116689

REPOSITORIES: GEO

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Project description:Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic mutations in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic mutations in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA[Ser]Sec biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the underlying mechanisms of SEPSECS mutations, we generated a novel mouse model recapitulating the respective human pathogenic Y334C mutation in the murine Sepsecs gene (SepsecsY334C). Unlike in patients, homozygous mutant pups died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by inactivating mutations of the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in SepsecsY334C/Y334C mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of SepsecsY334C/Y334C mice with mice harboring a targeted mutation of the catalytically active site Sec to Cys in GPX4 surprisingly rescued perinatal death of SepsecsY334C/Y334C mice, showing that the cardio-respiratory defects of Sepsecs-mutant mice were caused by the lack of GPX4. Like in SepsecsY334C/Y334C mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA[Ser]Sec biosynthesis. Our findings imply that children with mutations in SEPSECS or GPX4 may benefit from treatments partially compensating for impaired GPX4 activity.

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Knockout of the selenocysteine tRNA (Trsp) gene in mouse macrophage

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