Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati OH 45267, USA.
Dis Model Mech. 2021 May 1;14(5). doi: 10.1242/dmm.048439. Epub 2021 May 24.
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.
原发性纤毛运动障碍（PCD）的病理学主要归因于运动纤毛的损伤。然而，PCD 患者的髓样细胞也存在令人费解的功能缺陷，而这些细胞缺乏运动纤毛。在这里，我们表明卷曲螺旋结构域蛋白 103（CCDC103），当发生突变时已知会导致 PCD 的基因之一，是髓样细胞增殖和定向迁移所必需的。CCDC103 在人类髓样细胞中表达，在那里它与细胞质微管共定位。斑马鱼 ccdc103/schmalhans（smh）突变体的巨噬细胞和中性粒细胞增殖减少，细胞形态异常圆形，无法有效地迁移到无菌伤口部位，所有这些都与细胞质微管稳定性丧失一致。此外，我们证明了 CCDC103 与精子相关抗原 6（SPAG6）之间的直接相互作用也促进了微管稳定性，而来自 PCD 患者的 CCDC103 突变会破坏这种相互作用，并且 spag6 斑马鱼突变体再现了 smh 突变体中观察到的髓样缺陷。总之，我们阐明了一种独立于运动纤毛的机制，以解释 PCD 患者髓样细胞的功能缺陷。本文附有该论文第一作者的第一人称采访。
