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

Martinez-Heredia, Victor, Blackwell, Danielle, Sebastian, Sujith, Pearson, Timothy, Mok, Gi Fay ORCID: https://orcid.org/0000-0002-5202-9062, Mincarelli, Laura, Utting, Charlotte, Folkes, Leighton, Poeschl, Ernst, Macaulay, Iain, Mayer, Ulrike ORCID: https://orcid.org/0000-0003-2328-0052 and Münsterberg, Andrea ORCID: https://orcid.org/0000-0002-4577-4240 (2023) Absence of the primary cilia formation gene Talpid3 impairs muscle stem cell function. Communications Biology, 6. ISSN 2399-3642

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Abstract

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 (TA3) is essential for primary cilia formation and Hedgehog (Hh) signalling. Here we use tamoxifen-inducible conditional deletion of TA3 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 TA3iSC-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 TA3, 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 TA3 and primary cilia are important for MuSC self-renewal and pharmacological treatment can efficiently restore muscle regeneration.

Item Type: Article
Additional Information: Funding Information: We thank Paul Thomas in the Henry Wellcome Cell Imaging Laboratory (UEA) for support with microscopy, Anita Scoones (Earlham Institute) for discussions of scRNA analysis, Peter Zammit (KCL) for sharing advice on myofiber isolation and Cheryll Tickle for sharing the TA floxed mice. V.M.-H., L.F., S.S. and T.P. were supported by MRC project grant, MR/R000549/1, to A.M. and U.M. D.B. was supported by a BBSRC NRPDTP studentship. G.F.M. was supported by BHF project grant, PG/19/76/34696. The authors acknowledge funding from the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, Core Capability Grant BB/CCG1720/1. Part of this work was delivered via the BBSRC National Capability in Genomics and Single Cell Analysis (BBS/E/T/000PR9816) at Earlham Institute.
Uncontrolled Keywords: medicine (miscellaneous),biochemistry, genetics and molecular biology(all),agricultural and biological sciences(all) ,/dk/atira/pure/subjectarea/asjc/2700/2701
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 24 Jan 2024 01:35
Last Modified: 24 Jan 2024 01:35
URI: https://ueaeprints.uea.ac.uk/id/eprint/94237
DOI: 10.1038/s42003-023-05503-9

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