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    ATP11C promotes the differentiation of pre-B cells into immature B cells but does not affect their IL-7-dependent proliferation
    (Springer, 2023) Yabas, Mehmet; Bostanci, Ayten; Aral, Seda
    The P4-type ATPases are believed to function as flippases that contribute to the organization of the asymmetric aminophospholipid distribution on the plasma membranes of eukaryotes by their ability to internalize specific phospholipids from the outer leaflet to the inner leaflet. Despite the existence of 14 members of the P4-type ATPases in humans and 15 in mice, their roles in the immune system have not been fully understood. So far, ATP11C was shown to be important for B cells, and mice deficient for ATP11C had a developmental arrest at the pro-B to pre-B cell transition stage of B cell development. Using an ATP11C-deficient pre-B cell line generated through CRISPR/Cas9 engineering, we here tested the role of ATP11C in pre-B cells in vitro and showed that ablation of ATP11C in pre-B cells causes a defect in the flippase activity. We further demonstrated that loss of ATP11C does not impede the proliferation of pre-B cells in response to IL-7. However, pre-B cells lacking ATP11C failed to differentiate into immature B cells upon removal of IL-7. These results suggest that disruption of lipid asymmetry by loss of ATP11C in pre-B cells may control the switch from proliferation to differentiation in pre-B cells.
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    Immunological Phenotyping of Mice with a Point Mutation in Cdk4
    (Mdpi, 2023) Yabas, Mehmet; Hoyne, Gerard F.
    Cyclin-dependent kinases (CDKs) play a crucial role in regulation of the mammalian cell cycle. CDK4 and CDK6 control the G1/S restriction checkpoint through their ability to associate with cyclin D proteins in response to growth factor signals. CDK4 deficiency in mice gives rise to a range of endocrine-specific phenotypes including diabetes, infertility, dwarfism, and atrophy of the anterior pituitary. Although CDK6 deficiency can cause thymic atrophy due to a block in the double-negative (DN) to double-positive (DP) stage of T cell development, there are no overt defects in immune cell development reported for CDK4-deficient mice. Here, we examined the impact of a novel N-ethyl-N-nitrosourea-induced point mutation in the gene encoding CDK4 on immune cell development. Mutant mice (Cdk4(wnch/wnch)) showed normal development and differentiation of major immune cell subsets in the thymus and spleen. Moreover, T cells from Cdk4(wnch/wnch) mice exhibited normal cytokine production in response to in vitro stimulation. However, analysis of the mixed bone marrow chimeras revealed that Cdk4(wnch/wnch)-derived T cell subsets and NK cells are at a competitive disadvantage compared to Cdk4(+/+)-derived cells in the thymus and periphery of recipients. These results suggest a possible role for the CDK4(wnch) mutation in the development of some immune cells, which only becomes apparent when the Cdk4(wnch/wnch) mutant cells are in direct competition with wild-type immune cells in the mixed bone marrow chimera.