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Molecular and Cellular Biology, July 2003, p. 5043-5055, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.5043-5055.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of the Mouse Rho-Associated Kinase 2 Gene Results in Intrauterine Growth Retardation and Fetal Death

Dean Thumkeo, Jeongsin Keel,{dagger} Toshimasa Ishizaki, Masaya Hirose,{ddagger} Kimiko Nonomura, Hiroko Oshima, Masanobu Oshima, Makoto M. Taketo, and Shuh Narumiya*

Department of Pharmacology, Kyoto University Faculty of Medicine, Sakyo-ku, Kyoto 606-8501, Japan

Received 12 December 2002/ Returned for modification 31 January 2003/ Accepted 28 April 2003

Rho-associated kinase (ROCK), including the ROCK-I and ROCK-II isoforms, is a protein kinase involved in signaling from Rho to actin cytoskeleton. However, in vivo functions of each ROCK isoform remain largely unknown. We generated mice deficient in ROCK-II by gene targeting. ROCK-II-/- embryos were found at the expected Mendelian frequency until 13.5 days postcoitum, but approximately 90% died thereafter in utero. ROCK-II-/- mice of both genders that survived were born runts, subsequently developed without gross abnormality, and were fertile. Whole-mount staining for a knocked-in lacZ reporter gene revealed that ROCK-II was highly expressed in the labyrinth layer of the placenta. Disruption of architecture and extensive thrombus formation were found in the labyrinth layer of ROCK-II-/- mice. While no obvious alteration in actin filament structures was found in the labyrinth layer of ROCK-II-/- placenta and stress fibers were formed in cultured ROCK-II-/- trophoblasts, elevated expression of plasminogen activator inhibitor 1 was found in ROCK-II-/- placenta. These results suggest that ROCK-II is essential in inhibiting blood coagulation and maintaining blood flow in the endothelium-free labyrinth layer and that loss of ROCK-II leads to thrombus formation, placental dysfunction, intrauterine growth retardation, and fetal death.

* Corresponding author. Mailing address: Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan. Phone: 81-75-753-4392. Fax: 81-75-753-4693. E-mail: snaru{at}mfour.med.kyoto-u.ac.jp.

{dagger} Died on 6 September 2000.

{ddagger} Present address: Department of Gynecology, Shiga University of Medical Science, Ohtsu 520-2192, Japan.

Molecular and Cellular Biology, July 2003, p. 5043-5055, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.5043-5055.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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