Ggt1-flox Mouse

Ggt1, gamma-glutamyltransferase 1, is a critical enzyme involved in the hydrolysis and/or transfer of gamma-glutamyl groups of glutathione, which helps maintain cysteine levels in plasma [3]. It is associated with multiple biological pathways, influencing processes related to oxidative stress regulation and immune-related functions. Genetic models, such as knockout mouse models, are valuable for studying its function.

In mouse retinal ganglion cells, Ggt1 knockdown leads to serious cell damage, aberrant iron homeostasis, and oxidative stress, while its overexpression alleviates these effects. Ggt1 interacts with glutamate cysteine ligase catalytic subunit (GCLC) to inhibit autophagy and ferroptosis, which are associated with glaucoma pathogenesis [1].

In a mouse model of neutropenia bearing EL4 lymphoma, administration of recombinant G-CSF increases the number of myeloid-derived suppressor cells (MDSCs) and attenuates the anti-cancer effect of chemotherapy. RNA sequencing shows that G-CSF enhances the immunosuppressive function of MDSCs by upregulating Ggt1. Targeting Ggt1 with GGsTop can prevent G-CSF-induced tumor growth without affecting myelopoiesis [4].

Ggt1(dwg/dwg) mice, a model for hereditary γ-glutamyltransferase deficiency with a nucleotide deletion in the Ggt1 gene, exhibit reduced GGT1 activity, altered GSH levels in different tissues, and phenotypes like dwarfism, cataract, and coat color abnormality. These abnormalities can be reversed by N-acetyl-L-cysteine [2].

In conclusion, Ggt1 plays essential roles in maintaining cellular redox balance, suppressing ferroptosis and autophagy, and modulating the immunosuppressive function of MDSCs. Studies using Ggt1-related mouse models, like Ggt1(dwg/dwg) mice and those manipulated in the context of G-CSF-MDSC interactions, have provided insights into its functions in glaucoma and cancer-related conditions, respectively.