The Heterotaxy Gene CCDC11 is Essential for Cytokinesis and Cell-Cell Adhesion via RhoA Regulation

Saurabh Kulkarni, Rachel E. Stephenson, Sarah Amalraj, Ewelina Betleja, James J. Moresco, John R. Yates, Moe R. Mahjoub, Ann L. Miller, Mustafa K. Khokha

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in CCDC11 have been identified in multiple patients with heterotaxy (Htx), a disorder of left-right (LR) patterning of the internal organs. In Xenopus, depletion of Ccdc11 causes defects in LR patterning, recapitulating the patient phenotype. Upon Ccdc11 depletion, normally monociliated cells of the Left-Right Organizer (LRO) exhibit multiple cilia per cell. Unexpectedly, we found that Ccdc11 is necessary for successful cytokinesis, and the multiciliation observed in Ccdc11-depleted cells was due to failed cytokinesis. Furthermore, CCDC11 depletion alters cell-cell adhesion with reduction in junctional localization of adhesion molecules. The small GTPase RhoA is critical for cytokinesis and cell-cell adhesion. Because the CCDC11 depletion phenotypes are reminiscent of RhoA loss of function, we investigated a possible connection to regulation of RhoA signaling. We demonstrate that CCDC11 is localized to the cytokinetic contractile ring overlapping with RhoA during cytokinesis and regulates total RhoA protein levels. Our results suggest that CCDC11 connects cytokinesis and LR patterning via RhoA regulation, providing a potential mechanism for heterotaxy disease pathogenesis.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Oct 24 2018
Externally publishedYes

Keywords

  • cilia
  • congenital heart disease
  • cytokinesis
  • left-right patterning
  • mitosis
  • RhoA
  • Xenopus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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