Abstract
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 Ca2+ channels (VGCCs), Connexin-43 based gap junctions, and Ca2+ release activated Ca2+ (CRAC) channels. 4-Dimensional Ca2+ imaging reveals that the Sonic hedgehog-responsive mesenchymal cells display synchronized Ca2+ oscillations, which expand progressively in area during feather elongation. Inhibiting VGCCs, gap junctions, or Sonic hedgehog signaling alters the mesenchymal Ca2+ landscape, cell movement patterns and feather bud elongation. Ca2+ 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 Ca2+ profile among cells, thereby coordinating cell movement patterns.
Highlights
Collective cell migration mediates multiple tissue morphogenesis processes
Endogenous directcurrent (DC) electric fields (EFs) have been detected during embryogenesis/regeneration in eukaryotes and these EFs were implicated in instructing cells with directional or positional information[7,8,9,10]
We hypothesize that tissue endogenous bioelectric signals mediated by ion channels, exchangers and pumps may carry out the signal relay function in mesenchymal cells during feather elongation
Summary
Collective cell migration mediates multiple tissue morphogenesis processes. Yet how multidimensional mesenchymal cell movements are coordinated remains mostly unknown. Inhibiting VGCCs, gap junctions, or Sonic hedgehog signaling alters the mesenchymal Ca2+ landscape, cell movement patterns and feather bud elongation. These authors contributed : Ang Li, Jung-Hwa Cho. Collective cell migrations play key roles in gastrulation, organogenesis, wound healing, and immune responses, as well as pathological processes including chronic inflammation and cancer invasion[1,2]. Feather bud elongation in chicken dorsal skin explants is a very robust and precise biological process, even without the embryonic microenvironment[14,15] The robustness of this process implies the maintenance of localized and stringent molecular mechanisms for coordinating collective cell behaviors. We hypothesize that tissue endogenous bioelectric signals mediated by ion channels, exchangers and pumps may carry out the signal relay function in mesenchymal cells during feather elongation
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