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Arrested natural killer cell development associated with transgene insertion into the Atf2 locus
Sungjin Kim1, Yun-Jeong Song, Darryl A Higuchi
1Howard Hughes Medical Institute, the Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Abstract:
Natural killer (NK) cell development in the bone marrow is not fully understood. Following lineage commitment, these cells appear to advance through a series of developmental stages that are beginning to be characterized. We previously reported a selective deficiency of NK cells in a C57BL/6 mouse with a transgenic construct consisting of the cDNA for the Ly49A major histocompatibility complex (MHC) class 1-specific inhibitory receptor driven by the granzyme A gene. This mouse has few NK cells in peripheral tissues with relative preservation of other immune cells, including T and B cells. Herein we demonstrate that these mice have an accumulation of NK cells with an immature phenotype in the bone marrow, consistent with a block at a previously proposed stage in normal NK-cell development. The phenotype is associated with transgenic insertion into Atf2, the gene for the basic leucine zipper (bZIP) transcription factor family member ATF-2. Although analysis of Atf2-null NK cells shows no defect, the transgenic mice express abnormal truncated Atf2 transcripts that may mediate a repressor effect because ATF2 can heterodimerize with other bZIP molecules. The defect is cell intrinsic, suggesting that certain bZIP molecules play significant roles in NK-cell development.
Insights
Natural killer (NK) cell development is clarified by a study showing immature NK cells accumulate in the bone marrow due to a genetic defect. This suggests basic leucine zipper (bZIP) transcription factors are crucial for normal NK cell maturation.
Area of Science:
- Immunology
- Developmental Biology
- Genetics
Background:
- Natural killer (NK) cell development in bone marrow is not fully understood.
- NK cells progress through developmental stages after lineage commitment.
- A previously studied transgenic mouse model showed a selective deficiency of NK cells.
Purpose of the Study:
- To investigate the cause of selective NK cell deficiency in a transgenic mouse model.
- To characterize the developmental stage of the deficient NK cells.
- To identify the specific gene and molecular mechanism responsible for the developmental block.
Main Methods:
- Phenotypic analysis of NK cells in bone marrow and peripheral tissues of transgenic mice.
- Genetic analysis to identify the insertion site of the transgenic construct.
- Investigation of the role of the ATF2 gene and its transcripts in NK cell development.
Main Results:
- Transgenic mice exhibited an accumulation of immature NK cells in the bone marrow.
- The transgenic construct inserted into the Atf2 gene, leading to abnormal Atf2 transcripts.
- Atf2-null NK cells showed no developmental defect, but abnormal transcripts may exert a repressor effect.
Conclusions:
- A defect in NK cell development, characterized by an accumulation of immature cells, was observed in transgenic mice.
- Transgenic insertion into Atf2 causes abnormal Atf2 transcripts, potentially blocking NK cell development.
- Basic leucine zipper (bZIP) transcription factors, including ATF2, play significant roles in cell-intrinsic NK cell development.
