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Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma

Xu, Yang and Ashley, Terry and Brainerd, Elizabeth E. and Bronson, Roderick T. and Meyn, M. Stephen and Baltimore, David (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes and Development, 10 (19). pp. 2411-2422. ISSN 0890-9369. doi:10.1101/gad.10.19.2411.

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ATM, the gene mutated in the inherited human disease ataxia-telangiectasia, is a member of a family of kinases involved in DNA metabolism and cell-cycle checkpoint control. To help clarify the physiological roles of the ATM protein, we disrupted the ATM gene in mice through homologous recombination. Initial evaluation of the ATM knockout animals indicates that inactivation of the mouse ATM gene recreates much of the phenotype of ataxia-telangiectasia. The homozygous mutant (ATM-/-) mice are viable, growth-retarded, and infertile. The infertility of ATM-/- mice results from meiotic failure. Meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. Immune defects also are evident in ATM-/- mice, including reduced numbers of B220+CD43- pre-B cells, thymocytes, and peripheral T cells, as well as functional impairment of T-cell-dependent immune responses. The cerebella of ATM-/- mice appear normal by histologic examination at 3 to 4 months and the mice have no gross behavioral abnormalities. The majority of mutant mice rapidly develop thymic lymphomas and die before 4 months of age. These findings indicate that the ATM gene product plays an essential role in a diverse group of cellular processes, including meiosis, the normal growth of somatic tissues, immune development, and tumor suppression.

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Baltimore, David0000-0001-8723-8190
Additional Information:© 1996 Cold Spring Harbor Laboratory Press. The Authors acknowledge that six months after the full-issue publication date, the Article will be distributed under a Creative Commons CC-BY-NC License (Attribution-NonCommercial 4.0 International License, Received July 26, 1996; revised version accepted August 13, 1996. We thank Drs. W. Sha, and J. Jacob for providing immunization reagents and helpful discussion, Dr. M.A. Handel for advice on histologic studies of spermatogenesis, A.W. Plug for help with meiotic studies, Drs. Peter Moens and Barbara Spyrogopholus for anti-Corl antibodies, and Brad Margus of the A-T Children's Project for his interest and support. This project was supported by National Institutes of Health (NIH) grants to D.B., CA-60592 to M.S.M. and GM-49779 to T.A. Y.X. was supported by a postdoctoral fellowship from the Cancer Research Fund of Damon Runyon-Walter Winchell Foundation. D.B. is an American Cancer Society research professor. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
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Damon Runyon-Walter Winchell Cancer FundUNSPECIFIED
American Cancer SocietyUNSPECIFIED
Subject Keywords:Meiosis; lymphoid development; tumorigenesis; DNA damage
Issue or Number:19
Record Number:CaltechAUTHORS:20200422-151001347
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Official Citation:Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Y Xu, T Ashley, E E Brainerd, R T Bronson, M S Meyn, and D Baltimore Genes Dev. October 1, 1996 10: 2411-2422; doi:10.1101/gad.10.19.2411
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102741
Deposited By: George Porter
Deposited On:22 Apr 2020 22:27
Last Modified:16 Nov 2021 18:15

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