The Heterotaxy Gene <i>CCDC11</i> Is Important for Cytokinesis via <scp>RhoA</scp> Regulation
Mutations in CCDC11 (cfap53) 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, monociliated cells of the Left-Right Organizer (LRO) exhibit multiple cilia per cell. Unexpectedly, we found that Ccdc11 is necessary for successful cytokinesis, explaining the multiciliation phenotype observed in Ccdc11-depleted cells. The small GTPase RhoA is critical for cytokinesis, and our Ccdc11 depletion phenotypes are reminiscent of RhoA loss of function. Here, we demonstrate that during cytokinesis CCDC11 is localized to the cytokinetic contractile ring overlapping with RhoA, and CCDC11 regulates total RhoA protein levels. Our results connect CCDC11 to cytokinesis and LR patterning via RhoA regulation, providing a potential mechanism for heterotaxy disease pathogenesis.
Authors
- Saurabh S. Kulkarni (ORCID: https://orcid.org/0000-0002-0882-6478)
- Angelo B. Arrigo (ORCID: https://orcid.org/0000-0002-1136-1085)
- Sarah Amalraj
- Rachel E. Stephenson (ORCID: https://orcid.org/0000-0001-8319-6448)
- James J. Moresco (ORCID: https://orcid.org/0000-0003-1178-1642)
- Mustafa K. Khokha (ORCID: https://orcid.org/0000-0002-9846-7076)
- Ann L. Miller (ORCID: https://orcid.org/0000-0002-7293-764X)
- Moe R. Mahjoub (ORCID: https://orcid.org/0000-0001-8129-7464)
- Ewelina Betleja
- John R. Yates (ORCID: https://orcid.org/0000-0002-8215-7276)
Institutions
- Scripps Research Institute (US)
- Washington University in St. Louis (US)
- University of Michigan (US)
- Yale University (US)
- Pediatrics and Genetics (US)
- University of Virginia (US)
Publication Details
- Journal
- Cytoskeleton
- Published
- 2024-10-31
- DOI
- https://doi.org/10.1002/cm.21952
- Citations
- 3
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.65
Funders
- National Science Foundation
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development