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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #147043
Title: INHIBITION OF RHO FAMILY GTPASES BY RHO GDP DISSOCIATION INHIBITOR DISRUPTS CARDIAC MORPHOGENESIS AND INHIBITS CARDIOMYOCYTE PROLIFERATION

Author
item WEI, LEI - BAYLOR COLLEGE MED
item IMANAKA-YOSHIDA, KYOKO - MIE UNIV SCHOOL MED
item WANG, LU - BAYLOR COLLEGE MED
item ZHAN, SONG - BAYLOR COLLEGE MED
item SCHNEIDER, MICHAEL - BAYLOR COLLEGE MED
item DEMAYO, FRANCESCO - BAYLOR COLLEGE MED
item Schwartz, Robert

Submitted to: Development
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/8/2002
Publication Date: 4/1/2002
Citation: Wei, L., Imanaka-Yoshida, K., Wang, L., Zhan, S., Schneider, M.D., DeMayo, F.J., Schwartz, R.J. 2002. Inhibition of Rho family GTPases by Rho GDP dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation. Development. 129(7):1705-1714.

Interpretive Summary: An increased expression of the inhibitor of Rho family cellular signaling, RhoGDI alpha, had a potent detrimental effect on formation of the mouse embryonic heart. The embryonic heart was blocked during cardiac looping a critical stage demarcating the cardiac chambers. More directly, excess RhoGDI alpha blocked myocyte proliferation reducing the thickening of the cardiac free walls.

Technical Abstract: Studies of Rho GTPases in Drosophila and Xenopus suggest that Rho family proteins may play an important role in embryogenesis. A reverse genetic approach was employed to explore the role of Rho GTPases in murine cardiac development. Cardiac-specific inhibition of Rho family protein activities was achieved by expressing Rho GDIalpha, a specific GDP dissociation inhibitor for Rho family proteins, using the alpha-myosin heavy chain promoter, active at embryonic day (E)8.0 during morphogenesis of the linear heart tube. RhoA, Rac1 and Cdc42 activities were significantly inhibited, as shown by decreased membrane translocation of these proteins in the transgenic hearts. Transgenic F1 mice for each of two independent lines expressing the highest levels of the transgene, died around E10.5. Homozygotes of the middle copy-number lines, in which Rho GDIalpha expression was increased four-fold over normal levels, were also embryonic lethal. Cardiac morphogenesis in these embryos was disrupted, with incomplete looping, lack of chamber demarcation, hypocellularity and lack of trabeculation. Cell proliferation was inhibited in the transgenic hearts, as shown by immunostaining with anti-phosphohistone H3, a marker of mitosis. In addition, ventricular hypoplasia was associated with up-regulation of p21, an inhibitor of cyclin-dependent kinases, and with down-regulation of cyclin A, while cell survival was not affected. These results reveal new biological functions for Rho family proteins as essential determinants of cell proliferation signals at looping and chamber maturation stages in mammalian cardiac development.