Inhibition of Rho family GTPases by Rho GDP dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation

Lei Wei, Kyoko Imanaka-Yoshida, Lu Wang, Song Zhan, Michael D. Schneider, Francesco J. DeMayo, Robert J. Schwartz

Research output: Contribution to journalArticle

76 Citations (Scopus)

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 GDIα, a specific GDP dissociation inhibitor for Rho family proteins, using the α-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 GDIα 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.

Original languageEnglish (US)
Pages (from-to)1705-1714
Number of pages10
JournalDevelopment (Cambridge)
Volume129
Issue number7
StatePublished - 2002
Externally publishedYes

Fingerprint

Guanine Nucleotide Dissociation Inhibitors
rho GTP-Binding Proteins
Morphogenesis
Cardiac Myocytes
rho-Specific Guanine Nucleotide Dissociation Inhibitors
Proteins
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21
Reverse Genetics
Cyclin A
Myosin Heavy Chains
Homozygote
Xenopus
Transgenes
Mitosis
Transgenic Mice
Drosophila
Embryonic Development
Cell Survival
Membrane Proteins

Keywords

  • Cardiac morphogenesis
  • Cardiomyocyte proliferation
  • Mouse
  • Rho GDI
  • Rho GTPases

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

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 (Cambridge), 129(7), 1705-1714.

Inhibition of Rho family GTPases by Rho GDP dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation. / Wei, Lei; Imanaka-Yoshida, Kyoko; Wang, Lu; Zhan, Song; Schneider, Michael D.; DeMayo, Francesco J.; Schwartz, Robert J.

In: Development (Cambridge), Vol. 129, No. 7, 2002, p. 1705-1714.

Research output: Contribution to journalArticle

Wei, L, Imanaka-Yoshida, K, Wang, L, Zhan, S, Schneider, MD, DeMayo, FJ & Schwartz, RJ 2002, 'Inhibition of Rho family GTPases by Rho GDP dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation', Development (Cambridge), vol. 129, no. 7, pp. 1705-1714.
Wei, Lei ; Imanaka-Yoshida, Kyoko ; Wang, Lu ; Zhan, Song ; Schneider, Michael D. ; DeMayo, Francesco J. ; Schwartz, Robert J. / Inhibition of Rho family GTPases by Rho GDP dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation. In: Development (Cambridge). 2002 ; Vol. 129, No. 7. pp. 1705-1714.
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