Early postnatal ataxia and abnormal cerebellar development in mice lacking Xeroderma pigmentosum Group A and Cockayne Syndrome Group B DNA repair genes
- Machiko Murai*,†,
- Yasushi Enokido*,†,‡,
- Naoko Inamura*,†,
- Masafumi Yoshino§,
- Yoshimichi Nakatsu§,¶,
- Gijsbertus T. J. van der Horst‖,
- Jan H. J. Hoeijmakers‖,
- Kiyoji Tanaka§, and
- Hiroshi Hatanaka*
- *Division of Protein Biosynthesis, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan; §Division of Cellular Genetics, Institute for Molecular and Cellular Biology, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan; and ‖Medical Genetics Center, Department of Cell Biology and Genetics, Erasmus University, Rotterdam P. O. Box 1738, 3000 DR Rotterdam, The Netherlands
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Edited by James E. Cleaver, University of California, San Francisco, CA, and approved September 10, 2001 (received for review June 29, 2001)
Abstract
Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are rare autosomal recessive disorders associated with a defect in the nucleotide excision repair (NER) pathway required for the removal of DNA damage induced by UV light and distorting chemical adducts. Although progressive neurological dysfunction is one of the hallmarks of CS and of some groups of XP patients, the causative mechanisms are largely unknown. Here we show that mice lacking both the XPA (XP-group A) and CSB (CS-group B) genes in contrast to the single mutants display severe growth retardation, ataxia, and motor dysfunction during early postnatal development. Their cerebella are hypoplastic and showed impaired foliation and stunted Purkinje cell dendrites. Reduced neurogenesis and increased apoptotic cell death occur in the cerebellar external granular layer. These findings suggest that XPA and CSB have additive roles in the mouse nervous system and support a crucial role for these genes in normal brain development.
Footnotes
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↵ † M.M., Y.E., and N.I. contributed equally to this work.
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↵ ‡ To whom reprint requests should be addressed. E-mail: enokido{at}protein.osaka-u.ac.jp.
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↵ ¶ Present address: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University 3-1-1 Maida, Higashi-ku, Fukuoka 812-8582, Japan.
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This paper was submitted directly (Track II) to the PNAS office.
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See commentary on page 12860.
- Abbreviations:
- XP,
- xeroderma pigmentosum;
- CS,
- Cockayne syndrome;
- NER,
- nucleotide excision repair;
- PC,
- Purkinje cell;
- TUNEL,
- terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling;
- Pn,
- postnatal day n;
- EGL,
- external granular layer
- Copyright © 2001, The National Academy of Sciences
