Abstract
The establishment of left-right (L-R) asymmetry in vertebrates is dependent on the sensory and motile functions of cilia during embryogenesis. Mutations in CCDC11 disrupt L-R asymmetry and cause congenital heart disease in humans, yet the molecular and cellular functions of the protein remain unknown. Here we demonstrate that Ccdc11 is a novel component of centriolar satellites-cytoplasmic granules that serve as recruitment sites for proteins destined for the centrosome and cilium. Ccdc11 interacts with core components of satellites, and its loss disrupts the subcellular organization of satellite proteins and perturbs primary cilium assembly. Ccdc11 colocalizes with satellite proteins in human multiciliated tracheal epithelia, and its loss inhibits motile ciliogenesis. Similarly, depletion of CCDC11 in Xenopus embryos causes defective assembly and motility of cilia in multiciliated epidermal cells. To determine the role of CCDC11 during vertebrate development, we generated mutant alleles in zebrafish. Loss of CCDC11 leads to defective ciliogenesis in the pronephros and within the Kupffer's vesicle and results in aberrant L-R axis determination. Our results highlight a critical role for Ccdc11 in the assembly and function of motile cilia and implicate centriolar satellite-associated proteins as a new class of proteins in the pathology of L-R patterning and congenital heart disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 48-63 |
| Number of pages | 16 |
| Journal | Molecular biology of the cell |
| Volume | 27 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2016 |
Funding
We thank S. Brody (Washington University, St. Louis, MO) for providing human tracheobronchial epithelial progenitor cells and S. Dutcher (Washington University) for careful reading of the manuscript. We also thank L. Solnica-Krezel and K. Monk (Washington University) for help with zebrafish experiments and J. Wang (Washington University) for help with some molecular biology experiments. We give a special thanks to T. Stearns (Stanford University, Stanford, CA) for helpful discussions regarding this project. This study was supported by funding from the Washington University Renal Division (93368) and the National Heart, Lung and Blood Institute (R01HL126239) to M.R.M.; from the National Institute of General Medical Sciences (R01GM0899) to B.J.M.; and from the National Center for Research Resources (5 P4 1RR011823) and National Institute of General Medical Sciences (8 P41 GM103533) to J.R.Y., III.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
