Gap junction adhesion is necessary for radial migration in the neocortex


Radial glia, the neuronal stem cells of the embryonic cerebral cortex, reside deep within the developing brain and extend radial fibres to the pial surface, along which embryonic neurons migrate to reach the cortical plate. Here we show that the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) are expressed at the contact points between radial fibres and migrating neurons, and acute downregulation of Cx26 or Cx43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell–cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibres as well as the subsequent translocation of the nucleus. These results indicate that gap junction adhesions are necessary for glial-guided neuronal migration, raising the possibility that the adhesive properties of gap junctions may have an important role in other physiological processes and diseases associated with gap junction function.

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Figure 1: Cx26 and Cx43 are localized to contact points between migrating neurons and radial glial fibres.
Figure 2: Knockdown of Cx26 or Cx43 impairs neuronal migration.
Figure 3: Rescue of connexin-shRNA induced migration phenotype by wild-type connexin and connexin mutants that make adhesions but not channels.
Figure 4: Gap junctions promote cortical cell adhesion and interact with the internal actin cytoskeleton.
Figure 5: Gap junction adhesions have a role in the stabilization of the migrating neuron’s leading process and in the translocation of the soma.


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We are grateful for ideas arising from discussions with G.M. Elias, members of the Kriegstein Laboratory, A. Alvarez-Buylla, J. L. Rubensetin and S. J. Pleasure, as well as manuscript and figure editing by G.M. Elias. We thank D. Laird for connexin plasmids, A. Lai for C6 cell lines, K. Hu for the actin–cherry plasmid, R. Vallee for the centrin II–dsRed plasmid, and W. Walantus, J. Agudelo and T. Calcagni for technical support. Artwork in Fig. 5h is by K. X. Probst. This work was supported by grants from the National Institutes of Health (to A.R.K.), the Sandler Family and Genentech Graduate Fellowship (to L.A.B.E.), the California Institute for Regenerative Medicine Graduate Fellowship (to L.A.B.E.), and the J.G. Bowes Research Fund.

Author Contributions L.A.B.E. conceived of and carried out all experiments except as noted below. D.D.W. developed methods for and carried out the cell transplant/cell autonomy experiments and the whole-cell patch clamp recordings in C6 cells. A.R.K., as the principle investigator, provided conceptual and technical guidance for all aspects of the project. L.A.B.E. wrote the manuscript. All authors discussed the results/experiments and revised/edited the manuscript.

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Correspondence to Laura A. B. Elias or Arnold R. Kriegstein.

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Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-14 with Legends (PDF 1420 kb)

Supplementary Video 1a

This file contains Supplementary Video 1a with 3D rotation of area in crosshair of Figure 1i. Rotation shows expression of Cx26 puncta (red, relevant puncta circled) at the interface between a Vimentin+ radial fiber (green) and a β-III tubulin+ migrating neuron (blue) (MOV 1052 kb)

Supplementary Video 1b

This file contains Supplementary Video 1b. 3D rotation in Supplementary Video 1a showing only Cx26 puncta (red, relevant puncta circled) and the β-III tubulin+ migrating neuron (blue) to highlight the localization of the puncta at the region of contact between the migrating neuron and the radial fiber (not shown) (MOV 1052 kb)

Supplementary Video 2a

This file contains Supplementary Video 2a with 3D rotation of area in crosshair of Figure 1j. Rotation shows expression of Cx43 puncta (red, relevant puncta circled) at the interface between a Vimentin+ positive radial fiber (green) and the leading branch of a β-III tubulin+ migrating neuron (blue) (MOV 1954 kb)

Supplementary Video 2b

This file contains Supplementary Video 2b. 3D rotation in Supplementary Video 2a showing only Cx43 puncta (red, relevant puncta circled) and the β-III tubulin+ migrating neuron (blue) to highlight the localization of the puncta at the region of contact between the leading branch of the migrating neuron and the radial fiber (not shown). (MOV 1954 kb)

Supplementary Video 3

This file contains Supplementary Video 3 showing time-lapse of control migrating neurons (see Fig. 5a for description). (MOV 2242 kb)

Supplementary Video 4

This file contains Supplementary Video 4 showing time-lapse of migrating neuron expressing Cx43-shRNA (see Fig. 5c for description). (MOV 1648 kb)

Supplementary Video 5

This file contains Supplementary Video 5 time-lapse of migrating neuron expressing Cx26-shRNA (see Fig. 5c for description). (MOV 1737 kb)

Supplementary Video 6

This file contains Supplementary Video 6 showing time-lapse of migrating neuron expressing Cx43T154A-EYFP and Tomato (see Fig. 5d for description). (MOV 1528 kb)

Supplementary Video 7

This file contains Supplementary Video 7 showing time-lapse of migrating neuron expressing Cx26T135A-EYFP and Tomato (see Figure 5f for description). (MOV 652 kb)

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Elias, L., Wang, D. & Kriegstein, A. Gap junction adhesion is necessary for radial migration in the neocortex. Nature 448, 901–907 (2007).

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