Arginine N-Methyltransferase 1 Is Required for Early Postimplantation Mouse Development, but Cells Deficient in the Enzyme Are Viable

doi:10.1128/MCB.20.13.4859-4869.2000

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Molecular and Cellular Biology, July 2000, p. 4859-4869, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Arginine N-Methyltransferase 1 Is Required for Early Postimplantation Mouse Development, but Cells Deficient in the Enzyme Are Viable

Maciej R. Pawlak, Christina A. Scherer, Jin Chen, Michael J. Roshon,^§ and H. Earl Ruley^*

Department of Microbiology and Immunology, Nashville, Tennessee

Received 10 February 2000/Accepted 5 April 2000

Protein arginine N-methyltransferases have been implicated in a variety of processes, including cell proliferation, signaltransduction, and protein trafficking. In this study, we havecharacterized essentially a null mutation induced by insertionof the U3 $beta$ Geo gene trap retrovirus into the second intron of themouse protein arginine N-methyltransferase 1 gene (Prmt1). cDNAsencoding two forms of Prmt1 were characterized, and the predictedprotein sequences were found to be highly conserved among vertebrates.Expression of the Prmt1- $beta$ geo fusion gene was greatest along themidline of the neural plate and in the forming head fold fromembryonic day 7.5 (E7.5) to E8.5 and in the developing centralnervous system from E8.5 to E13.5. Homozygous mutant embryos failedto develop beyond E6.5, a phenotype consistent with a fundamentalrole in cellular metabolism. However, Prmt1 was not required forcell viability, as the protein was not detected in embryonic stem(ES) cell lines established from mutant blastocysts. Low levelsof Prmt1 transcripts (approximately 1% of the wild-type level)were detected as assessed by a quantitative reverse transcription-PCRassay. Total levels of arginine N-methyltransferase activity andasymmetric N^G,N^G-dimethylarginine were reduced by 85 and 54%, respectively, whilelevels of hypomethylated substrates were increased 15-fold. Prmt1appears to be a major type I enzyme in ES cells, and in wild-typecells, most substrates of the enzyme appear to be maintained ina fully methylatedstate.

^* Corresponding author. Present address: Department of Microbiology and Immunology, Room AA4210 MCN, Vanderbilt University Schoolof Medicine, 1161 21st Ave. South, Nashville, TN 37232-2363. Phone:(615) 343-1379. Fax: (615) 343-7392. E-mail: ruleye{at}ctrvax.vanderbilt.edu.

Present address: Department of Microbiology, University of Washington, Seattle, WA98195.

Present address: Department of Medicine, Division of Rheumatology, Vanderbilt University School of Medicine, Nashville, TN37232-2363.

^§ Present address: Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC 28232-2861.

Molecular and Cellular Biology, July 2000, p. 4859-4869, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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