Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Noctor, S. C., Flint, A. C., Weissman, T. A., Dammerman, R. S. & Kriegstein, A. R. Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Malatesta, P., Hartfuss, E. & Gotz, M. Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127, 5253–5263 (2000)

    CAS  PubMed  Google Scholar 

  3. Rakic, P. Guidance of neurons migrating to the fetal monkey neocortex. Brain Res. 33, 471–476 (1971)

    Article  CAS  Google Scholar 

  4. Rakic, P. Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145, 61–83 (1972)

    Article  CAS  Google Scholar 

  5. Rakic, P. Specification of cerebral cortical areas. Science 241, 170–176 (1988)

    Article  ADS  CAS  Google Scholar 

  6. Gregory, W. A., Edmondson, J. C., Hatten, M. E. & Mason, C. A. Cytology and neuron–glial apposition of migrating cerebellar granule cells in vitro. J. Neurosci. 8, 1728–1738 (1988)

    Article  CAS  Google Scholar 

  7. Gadisseux, J. F., Kadhim, H. J., van den Bosch de Aguilar, P., Caviness, V. S. & Evrard, P. Neuron migration within the radial glial fiber system of the developing murine cerebrum: an electron microscopic autoradiographic analysis. Brain Res. Dev. Brain Res. 52, 39–56 (1990)

    Article  CAS  Google Scholar 

  8. Cameron, R. S. & Rakic, P. Identification of membrane proteins that comprise the plasmalemmal junction between migrating neurons and radial glial cells. J. Neurosci. 14, 3139–3155 (1994)

    Article  CAS  Google Scholar 

  9. Fishell, G. & Hatten, M. E. Astrotactin provides a receptor system for CNS neuronal migration. Development 113, 755–765 (1991)

    CAS  PubMed  Google Scholar 

  10. Adams, N. C., Tomoda, T., Cooper, M., Dietz, G. & Hatten, M. E. Mice that lack astrotactin have slowed neuronal migration. Development 129, 965–972 (2002)

    CAS  PubMed  Google Scholar 

  11. Anton, E. S., Marchionni, M. A., Lee, K. F. & Rakic, P. Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. Development 124, 3501–3510 (1997)

    CAS  PubMed  Google Scholar 

  12. Anton, E. S., Kreidberg, J. A. & Rakic, P. Distinct functions of α3 and αv integrin receptors in neuronal migration and laminar organization of the cerebral cortex. Neuron 22, 277–289 (1999)

    Article  CAS  Google Scholar 

  13. Nadarajah, B., Jones, A. M., Evans, W. H. & Parnavelas, J. G. Differential expression of connexins during neocortical development and neuronal circuit formation. J. Neurosci. 17, 3096–3111 (1997)

    Article  CAS  Google Scholar 

  14. Fushiki, S. et al. Changes in neuronal migration in neocortex of connexin43 null mutant mice. J. Neuropathol. Exp. Neurol. 62, 304–314 (2003)

    Article  CAS  Google Scholar 

  15. Huang, G. Y. et al. Gap junction-mediated cell–cell communication modulates mouse neural crest migration. J. Cell Biol. 143, 1725–1734 (1998)

    Article  CAS  Google Scholar 

  16. Lo, C. W., Waldo, K. L. & Kirby, M. L. Gap junction communication and the modulation of cardiac neural crest cells. Trends Cardiovasc. Med. 9, 63–69 (1999)

    Article  CAS  Google Scholar 

  17. Lin, J. H. et al. Connexin 43 enhances the adhesivity and mediates the invasion of malignant glioma cells. J. Neurosci. 22, 4302–4311 (2002)

    Article  CAS  Google Scholar 

  18. Oliveira, R. et al. Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas. BMC Cell Biol. 6, 7 (2005)

    Article  Google Scholar 

  19. Harris, A. L. Emerging issues of connexin channels: biophysics fills the gap. Q. Rev. Biophys. 34, 325–472 (2001)

    Article  CAS  Google Scholar 

  20. Dermietzel, R. et al. Differential expression of three gap junction proteins in developing and mature brain tissues. Proc. Natl Acad. Sci. USA 86, 10148–10152 (1989)

    Article  ADS  CAS  Google Scholar 

  21. Lo Turco, J. J. & Kriegstein, A. R. Clusters of coupled neuroblasts in embryonic neocortex. Science 252, 563–566 (1991)

    Article  ADS  CAS  Google Scholar 

  22. Bittman, K., Owens, D. F., Kriegstein, A. R. & LoTurco, J. J. Cell coupling and uncoupling in the ventricular zone of developing neocortex. J. Neurosci. 17, 7037–7044 (1997)

    Article  CAS  Google Scholar 

  23. Weissman, T. A., Riquelme, P. A., Ivic, L., Flint, A. C. & Kriegstein, A. R. Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex. Neuron 43, 647–661 (2004)

    Article  CAS  Google Scholar 

  24. Falk, M. M. Connexin-specific distribution within gap junctions revealed in living cells. J. Cell Sci. 113, 4109–4120 (2000)

    CAS  PubMed  Google Scholar 

  25. Beahm, D. L. et al. Mutation of a conserved threonine in the third transmembrane helix of α- and β-connexins creates a dominant-negative closed gap junction channel. J. Biol. Chem. 281, 7994–8009 (2006)

    Article  CAS  Google Scholar 

  26. Komuro, H. & Rakic, P. Intracellular Ca2+ fluctuations modulate the rate of neuronal migration. Neuron 17, 275–285 (1996)

    Article  CAS  Google Scholar 

  27. Giepmans, B. N. & Moolenaar, W. H. The gap junction protein connexin43 interacts with the second PDZ domain of the zona occludens-1 protein. Curr. Biol. 8, 931–934 (1998)

    Article  CAS  Google Scholar 

  28. Lin, R., Warn-Cramer, B. J., Kurata, W. E. & Lau, A. F. v-Src phosphorylation of connexin 43 on Tyr247 and Tyr265 disrupts gap junctional communication. J. Cell Biol. 154, 815–827 (2001)

    Article  CAS  Google Scholar 

  29. Giepmans, B. N. et al. Gap junction protein connexin-43 interacts directly with microtubules. Curr. Biol. 11, 1364–1368 (2001)

    Article  CAS  Google Scholar 

  30. Naus, C. C., Bechberger, J. F., Caveney, S. & Wilson, J. X. Expression of gap junction genes in astrocytes and C6 glioma cells. Neurosci. Lett. 126, 33–36 (1991)

    Article  CAS  Google Scholar 

  31. Lai, A. et al. Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cells. J. Cell Sci. 119, 532–541 (2006)

    Article  CAS  Google Scholar 

  32. Xu, X., Francis, R., Wei, C. J., Linask, K. L. & Lo, C. W. Connexin 43-mediated modulation of polarized cell movement and the directional migration of cardiac neural crest cells. Development 133, 3629–3639 (2006)

    Article  CAS  Google Scholar 

  33. Schaar, B. T. & McConnell, S. K. Cytoskeletal coordination during neuronal migration. Proc. Natl Acad. Sci. USA 102, 13652–13657 (2005)

    Article  ADS  CAS  Google Scholar 

  34. Tsai, J. W., Bremner, K. H. & Vallee, R. B. Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue. Nature Neurosci. 10, 970–979; advance online publication, doi:10.1038/nn1934 (8 July 2007)

  35. Wiencken-Barger, A. E., Djukic, B., Casper, K. B. & McCarthy, K. D. A role for Connexin43 during neurodevelopment. Glia 55, 675–686 (2007)

    Article  Google Scholar 

  36. Xu, X. et al. Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions. J. Cell Biol. 154, 217–230 (2001)

    Article  CAS  Google Scholar 

  37. Meyer, R. A., Laird, D. W., Revel, J. P. & Johnson, R. G. Inhibition of gap junction and adherens junction assembly by connexin and A-CAM antibodies. J. Cell Biol. 119, 179–189 (1992)

    Article  CAS  Google Scholar 

  38. Dulabon, L. et al. Reelin binds α3β1 integrin and inhibits neuronal migration. Neuron 27, 33–44 (2000)

    Article  CAS  Google Scholar 

  39. Schmid, R. S., Jo, R., Shelton, S., Kreidberg, J. A. & Anton, E. S. Reelin, integrin and DAB1 interactions during embryonic cerebral cortical development. Cereb. Cortex 15, 1632–1636 (2005)

    Article  Google Scholar 

  40. el-Sabban, M. E. & Pauli, B. U. Adhesion-mediated gap junctional communication between lung-metastatatic cancer cells and endothelium. Invasion Metastasis 14, 164–176 (1994)

    CAS  PubMed  Google Scholar 

  41. Ito, A. et al. A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J. Clin. Invest. 105, 1189–1197 (2000)

    Article  CAS  Google Scholar 

  42. Lois, C., Hong, E. J., Pease, S., Brown, E. J. & Baltimore, D. Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 295, 868–872 (2002)

    Article  ADS  CAS  Google Scholar 

  43. Saito, T. & Nakatsuji, N. Efficient gene transfer into the embryonic mouse brain using in vivo electroporation. Dev. Biol. 240, 237–246 (2001)

    Article  CAS  Google Scholar 

  44. Walantus, W., Elias, L. & Kriegstein, A. R. In utero intraventricular injection and electroporation of E16 rat embryos. J. Visualized Exp. 6〉 (2007)

  45. Elias, L. & Kriegstein, A. R. Organotypic slice culture of E18 rat brains. J. Visualized Exp.. 6〉 (2007)

Download references


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.

Author information

Authors and Affiliations


Corresponding authors

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

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing