TY - JOUR
T1 - Role of intraflagellar transport protein IFT140 in the formation and function of motile cilia in mammals
AU - Yap, Yi Tian
AU - Pan, Jiehong
AU - Xu, Jian
AU - Yuan, Shuo
AU - Niu, Changmin
AU - Zheng, Cheng
AU - Li, Wei
AU - Zhou, Ting
AU - Li, Tao
AU - Zhang, Yong
AU - Holtzman, Michael J.
AU - Pazour, Gregory J.
AU - Hess, Rex A.
AU - Kelly, Christopher V.
AU - Touré, Aminata
AU - Brody, Steven
AU - Zhang, Zhibing
N1 - Publisher Copyright:
© 2025. The Author(s).
PY - 2025/5/10
Y1 - 2025/5/10
N2 - 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.
AB - 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.
KW - Cilia
KW - Fertility
KW - Intraflagellar transport
KW - Sperm
UR - http://www.scopus.com/inward/record.url?scp=105005235813&partnerID=8YFLogxK
U2 - 10.1007/s00018-025-05710-z
DO - 10.1007/s00018-025-05710-z
M3 - Article
C2 - 40348912
AN - SCOPUS:105005235813
SN - 1420-682X
VL - 82
SP - 198
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 1
ER -