Sema3a-Nrp1 Signaling Mediates Fast-Twitch Myofiber Specificity of Tw2+ Cells

Dev Cell. 2019 Oct 7;51(1):89-98.e4. doi: 10.1016/j.devcel.2019.08.002. Epub 2019 Aug 29.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Differentiation
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Chlorocebus aethiops
  • Female
  • Gene Deletion
  • Gene Expression Regulation
  • Ligands
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism
  • Neuropilin-1 / metabolism*
  • PAX7 Transcription Factor / metabolism
  • Satellite Cells, Skeletal Muscle / metabolism*
  • Semaphorin-3A / metabolism*
  • Sequence Analysis, RNA
  • Signal Transduction*
  • Stem Cells / metabolism

Substances

  • Ligands
  • PAX7 Transcription Factor
  • Pax7 protein, mouse
  • Sema3a protein, mouse
  • Semaphorin-3A
  • Neuropilin-1