Role of intraflagellar transport protein IFT140 in the formation and function of motile cilia in mammals
Cilia are microtubular structures extending from the surface of most mammalian cells. They can be categorized as motile cilia and primary sensory cilia. Both types possess intraflagellar transport (IFT) machinery, composed of unique protein complexes that travel along the microtubules to deliver proteins for ciliary and flagellar assembly, disassembly, and homeostasis. Although the role of IFT in primary cilia formation has been well studied, little is known about its role in mammalian motile cilia assembly. We generated conditional knockout mice by breeding floxed Ift140 mice with the FOXJ1-Cre transgenic mouse line to specifically delete Ift140 from cells that assemble motile cilia. Mice with Ift140 deficiency did not have laterality defects or gross; however most died prior to sexual maturity. Those mutants that survived to adulthood were completely infertile. Males demonstrated abnormal spermatogenesis associated with reduced sperm count and motility, together with short length flagella, and abnormal morphology. Cilia length was diminished in the epithelial cells of the efferent ductules and airways. Cilia from cultured tracheal epithelial cells were also short and had reduced beat frequency (CBF). Ultrastructural studies revealed the presence of inner and outer dynein arms, but an abnormal central apparatus, and the accumulation of particles within the cilia. Overall, the short length and abnormal localization of ciliary proteins in Ift140 conditional mutants resulted in inadequate cilia function despite proper localization of the dynein motor complexes. We propose a key role of Ift140 for motile cilia assembly in certain tissues and suggest that genetic alterations of IFT140 could be associated with motile ciliopathies.
Authors
- Zhibing Zhang (ORCID: https://orcid.org/0000-0002-8615-4478)
- Rex A. Hess (ORCID: https://orcid.org/0000-0003-2649-3563)
- Yi Tian Yap (ORCID: https://orcid.org/0000-0001-6448-2748)
- Aminata Touré (ORCID: https://orcid.org/0000-0001-5629-849X)
- Changmin Niu (ORCID: https://orcid.org/0000-0002-0918-3566)
- Christopher V. Kelly (ORCID: https://orcid.org/0000-0003-0886-8691)
- Steven L. Brody (ORCID: https://orcid.org/0000-0002-0905-7527)
- Michael J. Holtzman (ORCID: https://orcid.org/0000-0001-8750-3716)
- Gregory J. Pazour (ORCID: https://orcid.org/0000-0002-6285-8796)
- Jiehong Pan (ORCID: https://orcid.org/0000-0003-2384-6845)
- Wei Li (ORCID: https://orcid.org/0000-0002-0940-8155)
- Yong Zhang (ORCID: https://orcid.org/0000-0001-8929-3345)
- Tao Li (ORCID: https://orcid.org/0000-0002-0660-2745)
- Cheng Zheng (ORCID: https://orcid.org/0000-0003-4593-6091)
- Jian Xu (ORCID: https://orcid.org/0000-0002-4251-6895)
- Ting Zhou (ORCID: https://orcid.org/0000-0002-0069-2639)
- Shuo Yuan (ORCID: https://orcid.org/0000-0003-1880-6611)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- International Rice Research Institute (PH)
- University of Massachusetts Chan Medical School (US)
- Shanghai Jiao Tong University (CN)
- Urbana University (US)
- Wayne State University (US)
- Washington University in St. Louis (US)
- Harbin Institute of Technology (CN)
- Yale University (US)
- Institut de Neurophysiopathologie (FR)
- Qingdao Institute of Bioenergy and Bioprocess Technology (CN)
- Institut pour l'avancée des biosciences (FR)
- Wuhan University of Science and Technology (CN)
- Huazhong University of Science and Technology (CN)
- Yangzhou University (CN)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2025-05-10
- DOI
- https://doi.org/10.1007/s00018-025-05710-z
- Citations
- 1
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- Foundation for the National Institutes of Health
- Agence Nationale de la Recherche