Ccdc103 promotes myeloid cell proliferation and migration independent of motile cilia

Abstract

The pathology of primary ciliary dyskinesia (PCD) is predominantly attributed to impairment of motile cilia. However, PCD patients also have perplexing functional defects in myeloid cells, which lack motile cilia. Here, we show that coiled-coil domain-containing protein 103 (CCDC103), one of the genes that, when mutated, is known to cause PCD, is required for the proliferation and directed migration of myeloid cells. CCDC103 is expressed in human myeloid cells, where it colocalizes with cytoplasmic microtubules. Zebrafish ccdc103/schmalhans (smh) mutants have macrophages and neutrophils with reduced proliferation, abnormally rounded cell morphology and an inability to migrate efficiently to the site of sterile wounds, all of which are consistent with a loss of cytoplasmic microtubule stability. Furthermore, we demonstrate that direct interactions between CCDC103 and sperm associated antigen 6 (SPAG6), which also promotes microtubule stability, are abrogated by CCDC103 mutations from PCD patients, and that spag6 zebrafish mutants recapitulate the myeloid defects observed in smh mutants. In summary, we have illuminated a mechanism, independent of motile cilia, to explain functional defects in myeloid cells from PCD patients. This article has an associated First Person interview with the first author of the paper.

The Ancient and Evolved Mouse Sperm-Associated Antigen 6 Genes Have Different Biologic Functions In Vivo

“…A change in binding partner profiles during evolution is supported by another recent study. In zebrafish, the SPAG6 protein, whose sequence is 80% identical to mouse SPAG6, associates with Ccdc103, a coiled-coil domain-containing protein related to primary ciliary [35]. However, in our direct yeast two-hybrid assay, neither SPAG6 nor SPAG6L interacted with Ccdc103 (Supplemental Figure S8), suggesting that even though Ccdc103 and SPAG6 interact in zebrafish, they do not interact in mice.…”

PCD Genes—From Patients to Model Organisms and Back to Humans

“…Interestingly, with the recent use of zebrafish as a model, it was shown that CCDC103, the protein associated with axonemal outer doublets, is also present in myeloid cells where it co-localizes with microtubules. Mutations in CCDC103 or SPAG6 reduce microtubule stability and myeloid cell proliferation and migration [277]. Myeloid cells do not assemble cilia [278], but surprisingly, some researchers reported that myeloid cells obtained from PCD-affected individuals have some functional alterations [279][280][281].…”