Lamin A‐mediated nuclear lamina integrity is required for proper ciliogenesis

• Published in: EMBO reports 2020-10, Vol.21 (10), p.e49680-n/a
• Main Authors: Fan, Jia‐Rong, You, Li‐Ru, Wang, Won‐Jing, Huang, Wei‐Syun, Chu, Ching‐Tung, Chi, Ya‐Hui, Chen, Hong‐Chen
• Format: Article
• Language: English
• Subjects: Actin; Actins; Cell Nucleus; Cilia; ciliogenesis; ciliopathy; Cytochalasin D; Defects; Depletion; Disruption; EMBO05; Fibroblasts; Filaments; Homeostasis; Integrity; Kinases; lamin; Lamin Type A - genetics; laminopathy; Lamins; Lamins - genetics; Monomers; Myosin; Nuclear Lamina; Nuclear structure; Pathogenesis; Progeria; Recruitment; Tubulin; Vertebrates
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201949680

The primary cilium is a sensory organelle that receives specific signals from the extracellular environment important for vertebrate development and tissue homeostasis. Lamins, the major components of the nuclear lamina, are required to maintain the nuclear structure and are involved in most nuclear activities. In this study, we show that deficiency in lamin A/C causes defective ciliogenesis, accompanied by increased cytoplasmic accumulation of actin monomers and increased formation of actin filaments. Disruption of actin filaments by cytochalasin D rescues the defective ciliogenesis in lamin A/C‐depleted cells. Moreover, lamin A/C‐deficient cells display lower levels of nesprin 2 and defects in recruiting Arp2, myosin Va, and tau tubulin kinase 2 to the basal body during ciliogenesis. Collectively, our results uncover a functional link between nuclear lamina integrity and ciliogenesis and implicate the malfunction of primary cilia in the pathogenesis of laminopathy. Synopsis Lamin A, a major component of the nuclear lamina, regulates ciliogenesis through maintaining actin homeostasis. These findings indicate that defects in primary cilia may be involved in the pathogenesis of laminopathies, such as Hutchinson‐Gilford progeria syndrome. Lamin A‐deficient cells, including fibroblasts derived from Hutchinson‐Gilford progeria syndrome patients, lamin A/C-depleted RPE cells, and tissues from Lmna −/− mice, display decreased cilia incidence and cilia length. In lamin A‐, nesprin 2‐ or importin 9‐deficient cells, defective ciliogenesis is accompanied by increased formation of actin filaments. Disruption of the actin filaments by cytochalasin D rescues ciliogenesis. Nuclear lamina integrity is important for recruiting Arp2 and myosin Va to the basal body during ciliogenesis. Graphical Abstract Lamin A, a major component of the nuclear lamina, regulates ciliogenesis through maintaining actin homeostasis. These findings indicate that defects in primary cilia may be involved in the pathogenesis of laminopathies, such as Hutchinson‐Gilford progeria syndrome.