Developmental Cell
Volume 51, Issue 1, 7 October 2019, Pages 89-98.e4
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Article
Sema3a-Nrp1 Signaling Mediates Fast-Twitch Myofiber Specificity of Tw2+ Cells

https://doi.org/10.1016/j.devcel.2019.08.002Get rights and content
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Highlights

  • Tw2+ cells are a type IIb/x fiber-specific muscle progenitor

  • Nrp1 is a membrane receptor enriched in Tw2+ cells compared to Pax7+ cells

  • Sema3a is a type-I-and-IIa-myofiber-specific chemorepellent that binds Nrp1

  • Overexpression of Sema3a in type IIb myofibers prevents Tw2+ cell fusion

Summary

We previously identified a unique population of interstitial muscle progenitors, marked by expression of the Twist2 transcription factor, which fuses specifically to type IIb/x fast-twitch myofibers. Tw2+ progenitors are distinct from satellite cells, a muscle progenitor that expresses Pax7 and contributes to all myofiber types. Through RNA sequencing and immunofluorescence, we identify the membrane receptor, Nrp1, as a marker of Tw2+ cells but not Pax7+ cells. We also found that Sema3a, a chemorepellent ligand for Nrp1, is expressed by type I and IIa myofibers but not IIb myofibers. Using stripe migration assays, chimeric cell-cell fusion assays, and a Sema3a transgenic mouse model, we identify Sema3a-Nrp1 signaling as a major mechanism for Tw2+ cell fiber-type specificity. Our findings reveal an extracellular signaling mechanism whereby a cell-surface receptor for a chemorepellent confers specificity of intercellular fusion of a specific muscle progenitor with its target tissue.

Keywords

muscle stem cell
fiber-type specificity
semaphorin
Twist2
plexin
chemorepulsion
fusion
stripe assay

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