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

Victor Martinez-Heredia, Danielle Blackwell, Sujith Sebastian, Timothy Pearson, Gi Fay Mok, Laura Mincarelli, Charlotte Utting, Leighton Folkes, Ernst Poeschl, Iain Macaulay, Ulrike Mayer, Andrea Münsterberg

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1121
JournalCommunications Biology
Volume6
DOIs
Publication statusPublished - 4 Nov 2023

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