Skip to main content

Thank you for visiting nature.com. 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.

  • Letter
  • Published:

Lpd depletion reveals that SRF specifies radial versus tangential migration of pyramidal neurons

Nature Cell Biology volume 13, pages 989–995 (2011)Cite this article

Subjects

Abstract

During corticogenesis, pyramidal neurons (∼80% of cortical neurons) arise from the ventricular zone, pass through a multipolar stage to become bipolar and attach to radial glia1,2, and then migrate to their proper position within the cortex1,3. As pyramidal neurons migrate radially, they remain attached to their glial substrate as they pass through the subventricular and intermediate zones, regions rich in tangentially migrating interneurons and axon fibre tracts. We examined the role of lamellipodin (Lpd), a homologue of a key regulator of neuronal migration and polarization in Caenorhabditis elegans, in corticogenesis. Lpd depletion caused bipolar pyramidal neurons to adopt a tangential, rather than radial-glial, migration mode without affecting cell fate. Mechanistically, Lpd depletion reduced the activity of SRF, a transcription factor regulated by changes in the ratio of polymerized to unpolymerized actin. Therefore, Lpd depletion exposes a role for SRF in directing pyramidal neurons to select a radial migration pathway along glia rather than a tangential migration mode.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Lpd silencing impairs neuronal positioning.
Figure 2: Suppression of Lpd increases the number of tangentially oriented bipolar pyramidal neurons in the intermediate/subventricular zone.
Figure 3: Lpd-depleted bipolar pyramidal neurons migrate tangentially within the intermediate/subventricular zones but do not exhibit a change in cell fate.
Figure 4: Lpd affects the orientation of cortical bipolar cells through an SRF/MAL-dependent pathway.
Figure 5: Expression of MAL G-actin binding motifs (RPEL) rescues the Lpd-knockdown orientation and positioning defects of bipolar pyramidal neurons.

Similar content being viewed by others

References

  1. Ayala, R., Shu, T. & Tsai, L. H. Trekking across the brain: the journey of neuronal migration. Cell 128, 29–43 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Rakic, P. Developmental and evolutionary adaptations of cortical radial glia. Cereb. Cortex 13, 541–549 (2003).

    Article  PubMed  Google Scholar 

  3. Marin, O. & Rubenstein, J. L. Cell migration in the forebrain. Annu. Rev. Neurosci. 26, 441–483 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Han, J. et al. Reconstructing and deconstructing agonist-induced activation of integrin αIIbβ3. Curr. Biol. 16, 1796–1806 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Krause, M. et al. Lamellipodin, an Ena/VASP ligand, is implicated in the regulation of lamellipodial dynamics. Dev. Cell 7, 571–583 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Lafuente, E. M. et al. RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev. Cell 7, 585–595 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Michael, M., Vehlow, A., Navarro, C. & Krause, M. c-Abl, Lamellipodin, and Ena/VASP proteins cooperate in dorsal ruffling of fibroblasts and axonal morphogenesis. Curr. Biol. 20, 783–791 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Adler, C. E., Fetter, R. D. & Bargmann, C. I. UNC-6/Netrin induces neuronal asymmetry and defines the site of axon formation. Nat. Neurosci. 9, 511–518 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chang, C. et al. MIG-10/lamellipodin and AGE-1/PI3K promote axon guidance and outgrowth in response to slit and netrin. Curr. Biol. 16, 854–862 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Manser, J. & Wood, W. B. Mutations affecting embryonic cell migrations in Caenorhabditis elegans. Dev. Genet. 11, 49–64 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Quinn, C. C. et al. UNC-6/netrin and SLT-1/slit guidance cues orient axon outgrowth mediated by MIG-10/RIAM/lamellipodin. Curr. Biol. 16, 845–853 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Fode, C. et al. A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev. 14, 67–80 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hand, R. et al. Phosphorylation of Neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex. Neuron 48, 45–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Kriegstein, A. R. & Noctor, S. C. Patterns of neuronal migration in the embryonic cortex. Trends Neurosci. 27, 392–399 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Yokota, Y. et al. Radial glial dependent and independent dynamics of interneuronal migration in the developing cerebral cortex. PLoS One 2, e794 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sanchez-Alcaniz, J. A. et al. Cxcr7 controls neuronal migration by regulating chemokine responsiveness. Neuron 69, 77–90 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Wang, Y. et al. CXCR4 and CXCR7 have distinct functions in regulating interneuron migration. Neuron 69, 61–76 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lyulcheva, E. et al. Drosophila pico and its mammalian ortholog lamellipodin activate serum response factor and promote cell proliferation. Dev. Cell 15, 680–690 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Miralles, F., Posern, G., Zaromytidou, A. I. & Treisman, R. Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113, 329–342 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Posern, G. & Treisman, R. Actin’ together: serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol. 16, 588–596 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Johansen, F. E. & Prywes, R. Identification of transcriptional activation and inhibitory domains in serum response factor (SRF) by using GAL4-SRF constructs. Mol. Cell Biol. 13, 4640–4647 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Posern, G., Sotiropoulos, A. & Treisman, R. Mutant actins demonstrate a role for unpolymerized actin in control of transcription by serum response factor. Mol. Biol. Cell 13, 4167–4178 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vartiainen, M. K., Guettler, S., Larijani, B. & Treisman, R. Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL. Science 316, 1749–1752 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Elias, L. A., Turmaine, M., Parnavelas, J. G. & Kriegstein, A. R. Connexin 43 mediates the tangential to radial migratory switch in ventrally derived cortical interneurons. J. Neurosci. 30, 7072–7077 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Xie, Z. et al. Cep120 and TACCs control interkinetic nuclear migration and the neural progenitor pool. Neuron 56, 79–93 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Geneste, O., Copeland, J. W. & Treisman, R. LIM kinase and Diaphanous cooperate to regulate serum response factor and actin dynamics. J. Cell Biol. 157, 831–838 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schaeren-Wiemers, N. & Gerfin-Moser, A. A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100, 431–440 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Victorov, I. V. & Krukoff, T. L. Patterns of reaggregation and formation of linear aggregate chains in collagen-well cultures of dissociated mouse brain and spinal cord cells. Brain Res. 198, 167–182 (1980).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank R. Treisman for providing DNA constructs and R. Hayman for help with graphics. E.M.P. was supported by an NRSA grant F32-GM074507. This work was supported by financial support from a Koch Institute Development award and NIH grant # GM068678 to F.B.G.; L-H.T. is an investigator of Howard Hughes Medical Institute.

Author information

Author notes

  1. Elaine M. Pinheiro & Amy L. Norovich

    Present address: Present addresses: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA (E.M.P.); Columbia University, New York, New York 10027, USA (A.L.N.),

Authors and Affiliations

  1. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    Elaine M. Pinheiro, Amy L. Norovich, Marina Vidaki & Frank B. Gertler

  2. Department of Neurosurgery, Boston University School of Medicine, Boston, Massachusetts 02118, USA

    Zhigang Xie

  3. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    Li-Huei Tsai

  4. Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, USA

    Li-Huei Tsai

Authors
  1. Elaine M. Pinheiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhigang Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amy L. Norovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marina Vidaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Huei Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank B. Gertler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.M.P. designed experiments, analysed data and wrote the paper. Z.X. designed and carried out experiments. A.L.N. and M.V. carried out experiments. L-H.T. provided advice and commented on the manuscript. E.M.P., Z.X. and F.B.G. discussed the results and implications and commented on the manuscript at all stages. F.B.G. designed experiments, gave technical support and conceptual advice and revised the manuscript.

Corresponding author

Correspondence to Frank B. Gertler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 511 kb)

Supplementary Movie 1a

Supplementary Information (MOV 3326 kb)

Supplementary Movie 1b

Supplementary Information (MOV 2540 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pinheiro, E., Xie, Z., Norovich, A. et al. Lpd depletion reveals that SRF specifies radial versus tangential migration of pyramidal neurons. Nat Cell Biol 13, 989–995 (2011). https://doi.org/10.1038/ncb2292

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2292

This article is cited by

Search

Advanced search

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