A Critical Role for DNA End-Joining Proteins in Both Lymphogenesis and Neurogenesis

XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line. By gene-targeted mutation, we show that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J...

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Bibliographic Details
Published in:Cell 1998-12, Vol.95 (7), p.891-902
Main Authors: Gao, Yijie, Sun, Yi, Frank, Karen M., Dikkes, Pieter, Fujiwara, Yuko, Seidl, Katherine J., Sekiguchi, JoAnn M., Rathbun, Gary A., Swat, Wojciech, Wang, Jiyang, Bronson, Roderick T., Malynn, Barbara A., Bryans, Margaret, Zhu, Chengming, Chaudhuri, Jayanta, Davidson, Laurie, Ferrini, Roger, Stamato, Thomas, Orkin, Stuart H., Greenberg, Michael E., Alt, Frederick W.
Format: Article
Language:English
Subjects:
Animals
Antigens, Nuclear
Apoptosis
Body Patterning
Cell Cycle
Cell Differentiation
Cell Line
Central Nervous System - cytology
Central Nervous System - embryology
DNA Helicases
DNA Ligase ATP
DNA Ligases - genetics
DNA Ligases - metabolism
DNA Repair - radiation effects
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Embryonic and Fetal Development
Fibroblasts
Gene Rearrangement
Genes, Essential
Ku Autoantigen
Lymphocyte Subsets - cytology
Lymphocyte Subsets - immunology
Mice
Mice, Knockout
Neurons - cytology
Neurons - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Radiation, Ionizing
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Summary:XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line. By gene-targeted mutation, we show that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination. In mice, XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells. We find similar neuronal developmental defects in embryos that lack DNA ligase IV, an XRCC4-associated protein. Our findings demonstrate that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins and point to the general stage of neuronal development in which these proteins are necessary.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(00)81714-6