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1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
2 Cardiovascular Sciences Section, Baylor College of Medicine, Houston, TX 77030, USA
3 Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX 77030, USA
4 Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
5 Yale Child Health Research Center, Yale University School of Medicine, New Haven, CN, USA
6 Department of Pathology, Mie University, School of Medicine, Tsu, Mie, Japan
* These authors contributed equally to this work
Author for correspondence (e-mail: schwartz{at}bcm.tmc.edu)
Accepted May 12, 2001
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 Hensens node, and establishment of normal left-right asymmetry. Moreover, Y27632 induced precocious expression of cardiac
-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.
Key words: Rho kinase, Y27632, Cardia bifida, Cardiomyocyte differentiation, Chick
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