Gap junction adhesion dynamics in migrating neurons. Gap junction adhesive contacts stabilize the dominant leading process along radial fibres and provide an anchor in the dilation of the leading process before translocation of the soma/nucleus.

From Nature 448, 901-907 (2007).

Gap junctions are intercellular channels that connect the cytoplasm of adjacent cells to allow the direct passage of ions and small molecules. Most animal cells use gap junctions for cell-to-cell communication, which regulates many important biological processes. Recent studies have suggested a role for gap junctions in neural migration, but the underlying mechanism is still unclear. In Nature, Laura Elias and colleagues now report the striking finding that neural migration relies on the adhesive properties of gap junctions rather than on their channel properties.

During the development of the cerebral cortex, newly formed neurons migrate from their origin in the ventricular zone to the cortical plate, where they differentiate into pyramidal cells. Migration occurs along guiding radial glial fibres. However, the molecular players that mediate glia-neuron interactions have remained elusive. Elias et al. identified the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) as good candidates due to their ability to localize to the regions of contact between fibres and neurons. RNA interference-induced downregulation of Cx26 and Cx43 in intact developing rat brains impaired neural migration, demonstrating that gap junctions — and these connexins — are essential to this process.

Gap junctions could control neural migration in one of three ways: through the exchange of small molecules or current between cells; through the release of substrates such as ATP into the extracellular environment; or by the provision of cell–cell adhesive contacts. Elias et al. distinguished between these possibilities by selectively rescuing different gap junction functions in a Cx26 and Cx43 knockdown background. Surprisingly, dominant-negative connexin mutants that produce closed channels but still make adhesions rescued the migration of neurons to the cortical plate. The authors observed no migratory defects upon inhibition of Ca²⁺ waves — which relies on ATP release — further suggesting that gap junction channel properties do not contribute to migration. The authors excluded the involvement of C-terminal intracellular signalling and cytosolic protein interactions by using Cx26 and Cx43 lacking a C-terminal domain. Only connexins that were unable to make adhesions failed to rescue migration defects.

The behaviour of neurons migrating along radial glia, as well as the dynamics of connexin localization, were analysed using time-lapse live imaging. Neurons extended a bifurcated leading process and then translocated their soma into one prevailing branch as it dilated. While Cx43 localized to the stabilizing branch, Cx26 localized predominantly in the cell body, and then ahead of the moving nucleus. Thus, gap junction adhesions may stabilize the leading process of migrating neurons, which is important for directing movement, and be involved in subsequent nuclear translocation.

Together these results show that gap junctions are necessary for neural migration in the developing cortex, and report for the first time a gap junction function that is based on adhesion rather than channel activity. Furthermore, the authors suggest a role for gap junctions in the regulation of leading process branch stabilization along radial fibres and nuclear translocation. More research is needed to determine whether the adhesive properties of gap junctions regulate the migration of other cell types, and whether they may be important for other physiological and disease processes.

Author: Kim Baumann