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

RhoA is critical for cytokinesis and cell-cell adhesion. While we have made significant progress in identifying the regulators of RhoA, our understanding remains incomplete. In multiple patients with heterotaxy (Htx), a disorder of left-right (LR) patterning of the internal organs, mutations in CCDC11 were identified. In Xenopus, depletion of ccdc11 causes defects in LR patterning, recapitulating the patient9s phenotype. Interestingly, with ccdc11 depletion, normally monociliated cells of the Left-Right Organizer (LRO) exhibited multiple cilia per cell. While investigating this multiciliated phenotype, we unexpectedly discovered that ccdc11 is critical for cytokinesis. In addition, CCDC11 depletion alters cell-cell adhesion with loss of junctional adhesion molecules. Based on these phenotypes, reminiscent of RhoA loss of function, we demonstrate that CCDC11 colocalizes with RhoA during cytokinesis and regulates total RhoA protein levels. In conclusion, CCDC11 surprisingly connects cytokinesis and LR patterning via RhoA regulation, providing a potential mechanism for disease pathogenesis.