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Molecular and Cellular Biology, December 2003, p. 8519-8527, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8519-8527.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Fibrillarin Is Essential for Early Development and Required for Accumulation of an Intron-Encoded Small Nucleolar RNA in the Mouse

Kathryn Newton,1 Elisabeth Petfalski,2 David Tollervey,2 and Javier F. Cáceres1*

MRC Human Genetics Unit, Edinburgh EH4 2XU,1 Wellcome Trust Centre for Cell Biology, King's Buildings, Edinburgh EH9 3JR, United Kingdom2

Received 4 June 2003/ Returned for modification 21 July 2003/ Accepted 25 August 2003

Fibrillarin, a protein component of C/D box small nucleolar ribonucleoproteins (snoRNPs), directs 2'-O-methylation of rRNA and is also involved in other aspects of rRNA processing. A gene trap screen in embryonic stem (ES) cells resulted in an insertion mutation in the fibrillarin gene. This insertion generated a fusion protein that contained the N-terminal 132 amino acids of fibrillarin fused to a ß-galactosidase-neomycin phosphotransferase reporter. As a result, the N-terminal GAR domain was present in the fusion protein but the methyltransferase-like domain was missing. The ES cell line with the targeted fibrillarin allele was transmitted through the mouse germ line, creating heterozygous animals. Western blot analyses showed a reduction in fibrillarin protein levels in the heterozygous knockout animals. Animals homozygous for the mutation were inviable, and massive apoptosis was observed in early Fibrillarin-/- embryos, showing that fibrillarin is essential for development. Fibrillarin+/- live-born mice displayed no obvious growth defect, but heterozygous intercrosses revealed a reduced ratio of +/- to +/+ mice, showing that some of the Fibrillarin heterozygous embryos die in utero. Analyses of tissue samples and cultured embryonic fibroblasts showed no discernible alteration in pre-rRNA processing or the level of the U3 snoRNA. However, the level of the intron-encoded box C/D snoRNA U76 was clearly reduced. This suggests a high requirement for snoRNA synthesis during an early stage in development.

* Corresponding author. Mailing address: MRC Human Genetics Unit, Western General Hospital. Crewe Rd., Edinburgh EH4 2XU, Scotland, United Kingdom. Phone: (44) 131 467-8426. Fax: (44) 131 467-8456. E-mail: Javier.Caceres{at}hgu.mrc.ac.uk.

Molecular and Cellular Biology, December 2003, p. 8519-8527, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8519-8527.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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