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Homeoprotein Intercellular Transfer, the Hidden Face of Cell-Penetrating Peptides

  • Alain ProchiantzEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 683)

Abstract

Cell-Penetrating Peptides (CPPs) are small peptides internalized by live cells, gaining access to their cytoplasm and intracellular organelles (i.e., mitochondria, nucleus) and are used as pharmacological tools. This is indeed a very important issue, fully justifying the efforts of several groups to better understand the mechanisms of peptide transduction and to verify if and how this strategy can be translated into therapeutic improvements. However, the discovery of peptide transduction is a consequence of that of a novel signaling mechanism based on the intercellular transfer of homeoprotein transcription factors. Indeed, the first and probably most popular CPPs (Tat and Penetratin) correspond to domains that drive TAT (HIV) and homeoprotein transcription factors into the cells. These findings have fostered several studies on transduction and allowed the design of “nonnatural” CPPs. As useful as they are, these lines of research have, in general, neglected the fact that protein transduction is a signaling mechanism, in its own right, with important physiological functions. In this chapter, I describe some of these functions and propose that this class of signaling molecules, in particular homeoproteins, may also be used as therapeutic agents.

Key words

Signaling Homeoprotein transcription factors Morphogens Patterns Axon guidance Critical periods Plasticity Neurology Psychiatry 

Notes

Acknowledgments

This work was supported by Centre national de la Recherche Scientifique, Ecole normale supérieure and Collège de France. I want to thank Elizabeth Di Lullo for her useful comments and careful rereading of the manuscript.

References

  1. 1.
    Frankel AD, Bredt DS, Pabo CO. Tat protein from human immunodeficiency virus forms a metal-linked dimer. Science 1988;240:70–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Prochiantz A, Joliot A. Can transcription factors function as cell-cell signalling molecules? Nat Rev Mol Cell Biol 2003;4:814–9.PubMedGoogle Scholar
  3. 3.
    Lucas WJ, Bouche-Pillon S, Jackson DP, et al. Selective trafficking of KNOTTED1 homeodomain protein and its mRNA through plasmodesmata. Science 1995;270:1980–3.CrossRefPubMedGoogle Scholar
  4. 4.
    Tassetto M, Maizel A, Osorio J, Joliot A. Plant and animal homeodomains use convergent mechanisms for intercellular transfer. EMBO Rep 2005;6:885–90.CrossRefPubMedGoogle Scholar
  5. 5.
    Joliot A, Prochiantz A. Transduction peptides: from technology to physiology. Nat Cell Biol 2004;6:189–96.CrossRefPubMedGoogle Scholar
  6. 6.
    Cai C, Masumiya H, Weisleder N, et al. MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol 2009;11:56–64.CrossRefPubMedGoogle Scholar
  7. 7.
    Simeone A. Positioning the isthmic organizer where Otx2 and Gbx2 meet. Trends Genet 2000;16:237–40.CrossRefPubMedGoogle Scholar
  8. 8.
    Briscoe J, Pierani A, Jessell TM, Ericson J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 2000;101:435–45.CrossRefPubMedGoogle Scholar
  9. 9.
    Callaerts P, Halder G, Gehring WJ. PAX-6 in development and evolution. Annu Rev Neurosci 1997;20:483–532.CrossRefPubMedGoogle Scholar
  10. 10.
    Quiring R, Walldorf U, Kloter U, Gehring WJ. Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans. Science 1994;265:785–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Halder G, Callaerts P, Gehring WJ. Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 1995;267:1788–92.CrossRefPubMedGoogle Scholar
  12. 12.
    Chow RL, Altmann CR, Lang RA, Hemmati-Brivanlou A. Pax6 induces ectopic eyes in a vertebrate. Development 1999;126:4213–22.PubMedGoogle Scholar
  13. 13.
    Brunet I, Di Nardo AA, Sonnier L, Beurdeley M, Prochiantz A. The topological role of homeoproteins in the developing ­central nervous ­system. Trends Neurosci 2007;30:260–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Holcman D, Kasatkin V, Prochiantz A. Modeling homeoprotein intercellular transfer unveils a parsimonious mechanism for gradient and boundary formation in early brain development. J Theor Biol 2007;249:503–17.CrossRefPubMedGoogle Scholar
  15. 15.
    Lesaffre B, Joliot A, Prochiantz A, Volovitch M. Direct non-cell autonomous Pax6 activity regulates eye development in the zebrafish. Neural Dev 2007;2:2.CrossRefPubMedGoogle Scholar
  16. 16.
    Sperry RW. Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc Natl Acad Sci USA 1963;50:703–10.CrossRefPubMedGoogle Scholar
  17. 17.
    Flanagan JG, Vanderhaeghen P. The ephrins and Eph receptors in neural development. Annu Rev Neurosci 1998;21:309–45.CrossRefPubMedGoogle Scholar
  18. 18.
    Flanagan JG. Neural map specification by ­gradients. Curr Opin Neurobiol 2006;16:59–66.CrossRefPubMedGoogle Scholar
  19. 19.
    McLaughlin T, O’Leary DD. Molecular gradients and development of retinotopic maps. Annu Rev Neurosci 2005;28:327–55.CrossRefPubMedGoogle Scholar
  20. 20.
    Brunet I, Weinl C, Piper M, et al. The transcription factor Engrailed-2 guides retinal axons. Nature 2005;438:94–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Wizenmann A, Brunet I, Lam JSY, et al. Extracellular Engrailed participates in the topographic guidance of retinal axons in vivo. Neuron 2009;64(3):355–66.CrossRefPubMedGoogle Scholar
  22. 22.
    Sugiyama S, Di Nardo AA, Aizawa S, et al. Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity. Cell 2008;134:508–20.CrossRefPubMedGoogle Scholar
  23. 23.
    Kennedy DP, Courchesne E. The intrinsic functional organization of the brain is altered in autism. Neuroimage 2008;39:1877–85.CrossRefPubMedGoogle Scholar
  24. 24.
    Harrison PJ. Schizophrenia susceptibility genes and neurodevelopment. Biol Psychiatry 2007;61:1119–20.CrossRefPubMedGoogle Scholar
  25. 25.
    Walsh CA, Morrow EM, Rubenstein JL. Autism and brain development. Cell 2008;135:396–400.CrossRefPubMedGoogle Scholar
  26. 26.
    Simon HH, Thuret S, Alberi L. Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors. Cell Tissue Res 2004;318:53–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Sonnier L, Le Pen G, Hartmann A, et al. Progressive loss of dopaminergic neurons in the ventral midbrain of adult mice heterozygote for Engrailed1. J Neurosci 2007;27:1063–71.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Chaire des processus morphogénétiquesEcole normale supérieure and Collège de FranceParisFrance

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