Targeted disruption of the mouse rho-associated kinase 2 gene results in intrauterine growth retardation and fetal death.
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.
Thumkeo
Dean
D
Department of Pharmacology, Kyoto University Faculty of Medicine, Sakyo-ku, Kyoto 606-8501, Japan.
Keel
Jeongsin
J
Ishizaki
Toshimasa
T
Hirose
Masaya
M
Nonomura
Kimiko
K
Oshima
Hiroko
H
Oshima
Masanobu
M
Taketo
Makoto M
MM
Narumiya
Shuh
S
D000199:Actins / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D002478:Cells, Cultured; D005121:Extremities / Q000196:embryology / Q000473:pathology; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D005818:Genetic Engineering / Q000379:methods; D005838:Genotype; D006470:Hemorrhage / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D018878:Limb Buds; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D010920:Placenta / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000648:ultrastructure; D054460:rho-Associated Kinases
D000199:Actins; D047908:Intracellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases