Absence of the primary cilia formation gene Talpid3 impairs muscle stem cell function

• Published in: Communications biology 2023-11, Vol.6 (1), p.1121-1121, Article 1121
• Main Authors: Martinez-Heredia, Victor, Blackwell, Danielle, Sebastian, Sujith, Pearson, Timothy, Mok, Gi Fay, Mincarelli, Laura, Utting, Charlotte, Folkes, Leighton, Poeschl, Ernst, Macaulay, Iain, Mayer, Ulrike, Münsterberg, Andrea
• Format: Article
• Language: English
• Subjects: 13; 13/100; 14; 14/19; 42; 42/41; 45; 45/91; 631/208; 631/532; 631/532/2439; 64; 64/60; Animals; Basal lamina; Biology; Biomedical and Life Sciences; Cell cycle; Cell Cycle Proteins - genetics; Cell differentiation; Cell self-renewal; Cells, Cultured; Cilia; Cilia - genetics; Cilia - metabolism; Cytotoxicity; Drug therapy; Hedgehog protein; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Life Sciences; Mice; Muscles - cytology; Musculoskeletal system; Myoblasts; Phenotypes; Satellite Cells, Skeletal Muscle - metabolism; Signal transduction; Skeletal muscle; Stem cells; Stem Cells - cytology; Transcriptomics; Wnt protein
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-05503-9

Skeletal muscle stem cells (MuSC) are crucial for tissue homoeostasis and repair after injury. Following activation, they proliferate to generate differentiating myoblasts. A proportion of cells self-renew, re-enter the MuSC niche under the basal lamina outside the myofiber and become quiescent. Quiescent MuSC have a primary cilium, which is disassembled upon cell cycle entry. Ex vivo experiments suggest cilia are important for MuSC self-renewal, however, their requirement for muscle regeneration in vivo remains poorly understood. Talpid3 (TA 3 ) is essential for primary cilia formation and Hedgehog (Hh) signalling. Here we use tamoxifen-inducible conditional deletion of TA 3 in MuSC (iSC-KO) and show that regeneration is impaired in response to cytotoxic injury. Depletion of MuSC after regeneration suggests impaired self-renewal, also consistent with an exacerbated phenotype in TA 3iSC-KO mice after repeat injury. Single cell transcriptomics of MuSC progeny isolated from myofibers identifies components of several signalling pathways, which are deregulated in absence of TA 3 , including Hh and Wnt. Pharmacological activation of Wnt restores muscle regeneration, while purmorphamine, an activator of the Smoothened (Smo) co-receptor in the Hh pathway, has no effect. Together, our data show that TA 3 and primary cilia are important for MuSC self-renewal and pharmacological treatment can efficiently restore muscle regeneration. The Talpid3 gene, essential for primary cilia formation, is required for skeletal muscle stem cell (MuSC) self-renewal and loss of Talpid3 in MuSCs deregulates hedgehog and Wnt signalling pathways.