Calcium oscillations coordinate feather mesenchymal cell movement by SHH dependent modulation of gap junction networks

Collective cell migration mediates multiple tissue morphogenesis processes. Yet how multi-dimensional mesenchymal cell movements are coordinated remains mostly unknown. Here we report that coordinated mesenchymal cell migration during chicken feather elongation is accompanied by dynamic changes of bioelectric currents. Transcriptome profiling and functional assays implicate contributions from functional voltage-gated Ca(2+) channels (VGCCs), Connexin-43 based gap junctions, and Ca(2+) release activated Ca(2+) (CRAC) channels. 4-Dimensional Ca(2+) imaging reveals that the Sonic hedgehog-responsive mesenchymal cells display synchronized Ca(2+) oscillations, which expand progressively in area during feather elongation. Inhibiting VGCCs, gap junctions, or Sonic hedgehog signaling alters the mesenchymal Ca(2+) landscape, cell movement patterns and feather bud elongation. Ca(2+) oscillations induced by cyclic activation of opto-cCRAC channels enhance feather bud elongation. Functional disruption experiments and promoter analysis implicate synergistic Hedgehog and WNT/β-Catenin signaling in activating Connexin-43 expression, establishing gap junction networks synchronizing the Ca(2+) profile among cells, thereby coordinating cell movement patterns.