Editors' ChoiceCell Migration

Intracellular pH gradient guides cells

Sci. Signal.  28 Apr 2015:
Vol. 8, Issue 374, pp. ec106
DOI: 10.1126/scisignal.aab4054

Intracellular pH gradients may contribute to directional migration by affecting the activity of proteins that control cell motility. Using fluorescent intracellular pH biosensors, Tarbashevich et al. observed a dynamic intracellular pH gradient in migrating primordial germ cells (PGCs) in zebrafish embryos. The intracellular pH was highest at the leading edge when PGCs were polarized and actively migrating, but there was no intracellular pH gradient during normal pauses in PGC migration when the cells became unpolarized. Carbonic anhydrase 15b (Ca15b) is abundant in the cytoplasm of PGCs. Morpholino-mediated knockdown of Ca15b eliminated the pH gradient in migrating PGCs and caused improper migration of PGCs. Although some PGCs reached their target, many ended up at ectopic sites, indicating that directionality, but not motility, was impaired. PGCs in ca15b morphants changed direction more frequently than control PGCs, which migrate in a relatively straight path towards their target. A gradient of the chemokine Cxcl12a guides PGC migration. Knocking down Ca15b in embryos heterozygous for a mutation in cxcl12a increased the number of PGCs that failed to reach their target compared to knocking down Ca15b in wild-type embryos. Experiments in which Cxcl12a was knocked down or misexpressed or in which the ability of PGCs to respond to Cxcl12a was compromised demonstrated that the ability of the Cxcl12a gradient to promote the formation of the intracellular pH gradient depended on Ca15b. Comparing PGCs expressing tagged actin or a Rac1 biosensor in the ca15b morphants to those in wild-type embryos indicated that the pH gradient stimulated actin polymerization and activity of Rac1, a GTPase that promotes actin polymerization and is most active at high pH, at the leading edge. Thus, an extracellular chemokine gradient drives formation of an intracellular pH gradient in PGCs, and this promotes cytoskeletal reorganization necessary for directed migration toward the chemokine source.

K. Tarbashevich, M. Reichman-Fried, C. Grimaldi, E. Raz, Chemokine-dependent pH elevation at the cell front sustains polarity in directionally digrating zebrafish germ cells. Curr. Biol. 25, 1096–1103 (2015). [PubMed]