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

Dean Thumkeo; Jeongsin Keel; Toshimasa Ishizaki; Masaya Hirose; Kimiko Nonomura; Hiroko Oshima; Masanobu Oshima; Makoto M. Taketo; Shuh Narumiya

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

机译：小鼠Rho相关激酶2基因的定向破坏导致宫内发育迟缓和胎儿死亡。

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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.

机译：Rho相关激酶（ROCK），包括ROCK-I和ROCK-II同种型，是一种蛋白激酶，参与从Rho到肌动蛋白细胞骨架的信号传导。但是，每种ROCK同工型的体内功能仍然很大程度上未知。我们通过基因靶向产生了ROCK-II缺陷的小鼠。 ROCK-II ？/？胚胎以预期的孟德尔频率被发现，直到产后13.5天，但此后约90％在子宫内死亡。存活下来的两种性别的ROCK-II ？/？小鼠都是天生的矮小，随后发育而没有明显的异常，并且能够生育。敲入的 lacZ 报告基因的全部染色表明，ROCK-II在胎盘的迷宫层中高表达。在ROCK-II ？/？小鼠的迷宫层中发现了结构破坏和大量血栓形成。虽然在ROCK-II ？/？胎盘的迷宫层中肌动蛋白丝结构没有明显改变，但在培养的ROCK-II ？/？滋养层中形成了应力纤维，在ROCK-II ？/？胎盘中发现纤溶酶原激活物抑制剂1的表达升高。这些结果表明，ROCK-II对于抑制血液凝结和维持无内皮迷宫层中的血流至关重要，而ROCK-II的丢失会导致血栓形成，胎盘功能障碍，子宫内发育迟缓和胎儿死亡。 展开▼

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《Molecular and Cellular Biology》 |2003年第14期|共13页

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Dean Thumkeo; Jeongsin Keel; Toshimasa Ishizaki; Masaya Hirose; Kimiko Nonomura; Hiroko Oshima; Masanobu Oshima; Makoto M. Taketo; Shuh Narumiya;
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中图分类细胞生物学;

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1. Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway [J] . Chao WANG, Ruiming ZHANG, Le ZHOU, The Journal of Reproduction and Development . 2017,第6期

机译：宫内发育迟缓通过雷帕霉素途径的机制靶点促进大鼠胎儿肠道自噬

2. Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway [J] . Wang Chao, Zhang Ruiming, Zhou Le, The Journal of Reproduction and Development . 2017,第6期

机译：通过雷帕霉素途径的机制靶标促进大鼠胎儿肠道生长延迟促进胎儿肠道自血管

3. Slc7a7 disruption causes fetal growth retardation by downregulating Igf1 in the mouse model of lysinuric protein intolerance. [J] . Sperandeo MP, Annunziata P, Bozzato A, American Journal of Physiology . 2007,第1期

机译：Slc7a7破坏通过在赖氨酸尿酸蛋白不耐受的小鼠模型中下调Igf1导致胎儿发育迟缓。

4. Detection of Intrauterine Growth Retardation Using Fetal Abdominal Circumference [C] . Nithya J., Madheswaran M. Computer Technology and Development, 2009. ICCTD '09 . 2009

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5. It's a birth not a procedure: An ethnographic study of intrauterine fetal death in a labor and delivery unit of an American hospital setting [D] . Griffin, Catherine Wallis McLeod 2012

机译：这是分娩而不是程序：人种学研究在美国一家医院的分娩和分娩室进行的宫内胎儿死亡

6. Targeted Disruption of the Mouse Rho-Associated Kinase 2 Gene Results in Intrauterine Growth Retardation and Fetal Death [O] . Dean Thumkeo, Jeongsin Keel, Toshimasa Ishizaki, 2003

机译：小鼠Rho相关激酶2基因的靶向破坏导致宫内发育迟缓和胎儿死亡。

7. Targeted Disruption of the Mouse Rho-Associated Kinase 2 Gene Results in Intrauterine Growth Retardation and Fetal Death [O] . Thumkeo, Dean, Keel, Jeongsin, Ishizaki, Toshimasa, 2003

机译：小鼠Rho相关激酶2基因的靶向破坏导致宫内发育迟缓和胎儿死亡。

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5. DNA was isolated and purified, peptu00ecdeo, sequences of amino acids of human and murine sphk2, construction of recombinant DNA, host cell.Methods for producing a peptu00ecdeo of sphingosine kinase type 2 isoform of mouse and human.And to detect an agent or a drug that inhibits or promotes the activity of sphingosine kinase type 2, agent or product, methods for regulating a biological process in a mamu00ecfero,For the treatment or the improvement of a disease resulting from cell death increased or reduced cell proliferation.For the treatment or management of a disease resulting from reduced cell death or cell proliferation increased.And for the treatment or the improvement of a disease resulting from abnormal migration or motility of cells selected from the group consisted of cancer, restenose and diabetic neuropathy.Composition for the treatment or the improvement of UIMA disease resulting from cell death increased or reduced cell proliferation.Methods for screening for agents or [P] . 外国专利： BR0109827A . 2004-07-06

机译：分离纯化DNA，肽，人和鼠sphk2的氨基酸序列，重组DNA的构建，宿主细胞。小鼠和人2型鞘氨醇激酶2型亚型的肽的制备方法，并检测抑制或促进2型鞘氨醇激酶活性的药物或药物，药物或产物的调节方法，用于治疗哺乳动物的生物学过程的方法，用于治疗或改善由细胞死亡引起的疾病的方法，增加或减少的细胞增殖用于治疗或管理由减少的细胞死亡或细胞增殖引起的疾病，以及用于治疗或改善由癌症，再狭窄和糖尿病性神经病变组成的组中的细胞异常迁移或运动导致的疾病。用于治疗或改善由细胞死亡引起的UIMA疾病的组合物可增加或减少细胞增殖。

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

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