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Nucleic Acids Research Advance Access originally published online on August 31, 2006
Nucleic Acids Research 2006 34(16):4486-4494; doi:10.1093/nar/gkl609
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Nucleic Acids Research, 2006, Vol. 34, No. 16 4486-4494
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Transcriptional and phenotypic comparisons of Ppara knockout and siRNA knockdown mice

Angus T. De Souza*, Xudong Dai, Andrew G. Spencer1, Tom Reppen1, Ann Menzie1, Paula L. Roesch1, Yudong He, Michelle J. Caguyong, Sherri Bloomer, Hans Herweijer1, Jon A. Wolff1, James E. Hagstrom1, David L. Lewis1,*, Peter S. Linsley and Roger G. Ulrich

Rosetta Inpharmatics, a wholly owned subsidiary of Merck & Co. Inc. 401 Terry Avenue North, Seattle, WA 98109, USA 1 Mirus Bio Corporation, 505 S. Rosa Road Madison, WI 53719, USA

*To whom correspondence should be addressed. Tel: +1 608 441 2858; Fax: +1 608 441 2880; Email: dave.lewis{at}mirusbio.com

Received July 21, 2006. Revised August 3, 2006. Accepted August 4, 2006.

RNA interference (RNAi) has great potential as a tool for studying gene function in mammals. However, the specificity and magnitude of the in vivo response to RNAi remains to be fully characterized. A molecular and phenotypic comparison of a genetic knockout mouse and the corresponding knockdown version would help clarify the utility of the RNAi approach. Here, we used hydrodynamic delivery of small interfering RNA (siRNA) to knockdown peroxisome proliferator activated receptor alpha (Ppara), a gene that is central to the regulation of fatty acid metabolism. We found that Ppara knockdown in the liver results in a transcript profile and metabolic phenotype that is comparable to those of Ppara–/– mice. Combining the profiles from mice treated with the PPAR{alpha} agonist fenofibrate, we confirmed the specificity of the RNAi response and identified candidate genes proximal to PPAR{alpha} regulation. Ppara knockdown animals developed hypoglycemia and hypertriglyceridemia, phenotypes observed in Ppara–/– mice. In contrast to Ppara–/– mice, fasting was not required to uncover these phenotypes. Together, these data validate the utility of the RNAi approach and suggest that siRNA can be used as a complement to classical knockout technology in gene function studies.

*Correspondence may also be addressed to Angus T. De Souza. Tel: +1 425 246 5837; Email: angus_desouza{at}w-link.net


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