Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development.
The primary cilium is a cellular organelle that coordinates signaling pathways critical for cell proliferation, differentiation, survival, and homeostasis. Intraflagellar transport (IFT) plays a pivotal role in assembling primary cilia. Disruption and/or dysfunction of IFT components can cause multiple diseases, including skeletal dysplasia. However, the mechanism by which IFT regulates skeletogenesis remains elusive. Here, we show that a neural crest-specific deletion of intraflagellar transport 20 (Ift20) in mice compromises ciliogenesis and intracellular transport of collagen, which leads to osteopenia in the facial region. Whereas platelet-derived growth factor receptor alpha (PDGFRα) was present on the surface of primary cilia in wild-type osteoblasts, disruption of Ift20 down-regulated PDGFRα production, which caused suppression of PDGF-Akt signaling, resulting in decreased osteogenic proliferation and increased cell death. Although osteogenic differentiation in cranial neural crest (CNC)-derived cells occurred normally in Ift20-mutant cells, the process of mineralization was severely attenuated due to delayed secretion of type I collagen. In control osteoblasts, procollagen was easily transported from the endoplasmic reticulum (ER) to the Golgi apparatus. By contrast, despite having similar levels of collagen type 1 alpha 1 (Col1a1) expression, Ift20 mutants did not secrete procollagen because of dysfunctional ER-to-Golgi trafficking. These data suggest that in the multipotent stem cells of CNCs, IFT20 is indispensable for regulating not only ciliogenesis but also collagen intracellular trafficking. Our study introduces a unique perspective on the canonical and noncanonical functions of IFT20 in craniofacial skeletal development.
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030;
Kazuo
K
Noda
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030;
Megumi
M
Kitami
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030; Division of Orthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan;
Kohei
K
Kitami
Division of Bioprosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan;
Masaru
M
Kaku
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030; Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030 yoshihiro.komatsu@uth.tmc.edu.
Yoshihiro
Y
Komatsu
D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D001846:Bone Development / Q000502:physiology*; D002352:Carrier Proteins; D002478:Cells, Cultured; D019465:Craniofacial Abnormalities / Q000473:pathology / Q000503:physiopathology*; D005147:Facial Bones / Q000166:cytology / Q000502:physiology*; D005407:Flagella / Q000473:pathology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis / Q000502:physiology; D009432:Neural Crest / Q000502:physiology*; D010006:Osteoblasts / Q000502:physiology / Q000648:ultrastructure; D012886:Skull / Q000166:cytology / Q000502:physiology*
D002352:Carrier Proteins; C514104:Ift20 protein, mouse
PDGF signaling; cranial neural crest cells; intracellular trafficking; intraflagellar transport; primary cilia