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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #147041
Title: RHO KINASES PLAY AN OBLIGATORY ROLE IN VERTEBRATE EMBRYONIC ORGANOGENESIS

Author
item WEI, LEI - BAYLOR COLLEGE MED
item ROBERTS, WILMER - BAYLOR COLLEGE MED
item WANG, LU - BAYLOR COLLEGE MED
item YAMADA, MIHO - BAYLOR COLLEGE MED
item ZHANG, SHUXING - BAYLOR COLLEGE MED
item ZHAO, ZHIYONG - YALE UNIV SCHOOL MED
item RIVKEES, SCOTT - YALE UNIV SCHOOL MED
item Schwartz, Robert
item IMANAKA-YOSHIDA, KYOKO - MIE UNIV SCHOOL MED

Submitted to: Development
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/12/2001
Publication Date: 8/1/2001
Citation: Wei, L., Roberts, W., Wang, L., Yamada, M., Zhang, S., Zhao, Z., Rivkees, S.A., Schwartz, R.J., Imanaka-Yoshida, K. 2001. Rho kinases play an obligatory role in vertebrate embryonic organogenesis. Development. 128(15):2953-2962.

Interpretive Summary: We studied a drug, Y27632, that specifically inhibits a Rho dependent protein kinase. This drug was planned to be used in humans as a specific anti-hypertensive drug, because it causes vascular relaxation. We found that this drug is one of the most powerful embryo teratogens ever observed. Many avian and mammalian embryo defects were found that caused cardia bifida (two hearts) and loss of brain formation and laterality defects. This observation was presented before the Environmental Protection Agency and National Institutes of Health.

Technical Abstract: Rho-associated kinases (Rho kinases), which are downstream effectors of RhoA GTPase, regulate diverse cellular functions including actin cytoskeletal organization. We have demonstrated that Rho kinases also direct the early stages of chick and mouse embryonic morphogenesis. We observed that Rho kinase transcripts were enriched in cardiac mesoderm, lateral plate mesoderm and the neural plate. Treatment of neurulating embryos with Y27632, a specific inhibitor of Rho kinases, blocked migration and fusion of the bilateral heart primordia, formation of the brain and neural tube, caudalward movement of Hensen's node, and establishment of normal left-right asymmetry. Moreover, Y27632 induced precocious expression of cardiac alpha-actin, an early marker of cardiomyocyte differentiation, coincident with the upregulated expression of serum response factor and GATA4. In addition, specific antisense oligonucleotides significantly diminished Rho kinase mRNA levels and replicated many of the teratologies induced by Y27632. Thus, our study reveals new biological functions for Rho kinases in regulating major morphogenetic events during early chick and mouse development.