Affiliation:
1. The Division of Life Science and Key State Laboratory for Molecular Neuroscience, HKUST, Clear Water Bay, Hong Kong, PRC
Abstract
In the trunk of developing zebrafish embryos, adjacent myotome blocks transmit contractile force via myoseptal junctions (MJs), dynamic structures that connect the actin cytoskeleton of skeletal muscle cells to extracellular matrix components via transmembrane protein complexes in the sarcolemma. Here, we report that the endolysosomal ion channel, two-pore channel type 1 (TPC1), generates highly localized, non-propagating Ca2+ transients that play a distinct and required role in the capture and attachment of superficial slow skeletal muscle cells (SMCs) at MJs. Use of antisense morpholinos or CRISPR/Cas9 gene editing to disrupt tpcn1 gene expression resulted in abnormal MJ phenotypes including SMCs detaching from or crossing the myosepta. We also report that TPC1-decorated endolysosomes are dynamically associated with MJs in a microtubule-dependent manner, and that attenuating tpcn1 expression or function disrupted endolysosomal trafficking and resulted in an abnormal distribution of β-dystroglycan (a key transmembrane component of the dystrophin-associated protein complex). Together, our data suggest that localized TPC1-generated Ca2+ signals facilitate essential endolysosomal trafficking and membrane contact events, which help form and maintain MJs following the onset of SMC contractile activity.
Funder
Research Grants Council, University Grants Committee
Innovation and Technology Commission - Hong Kong
Publisher
The Company of Biologists
Cited by
2 articles.
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1. Two-pore channels: going with the flows;Biochemical Society Transactions;2022-08-12
2. First person – Keira L. Rice;Journal of Cell Science;2022-05-01