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The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis

Nature Neuroscience volume 7, pages 364–372 (2004)Cite this article

Abstract

Of 11 genes involved in nonspecific X-linked mental retardation (MRX), three encode regulators or effectors of the Rho GTPases, suggesting an important role for Rho signaling in cognitive function. It remains unknown, however, how mutations in Rho-linked genes lead to MRX. Here we report that oligophrenin-1, a Rho-GTPase activating protein that is absent in a family affected with MRX, is required for dendritic spine morphogenesis. Using RNA interference and antisense RNA approaches, we show that knock-down of oligophrenin-1 levels in CA1 neurons in rat hippocampal slices significantly decreases spine length. This phenotype can be recapitulated using an activated form of RhoA and rescued by inhibiting Rho-kinase, indicating that reduced oligophrenin-1 levels affect spine length by increasing RhoA and Rho-kinase activities. We further demonstrate an interaction between oligophrenin-1 and the postsynaptic adaptor protein Homer. Our findings provide the first insight into how mutations in a Rho-linked MRX gene may compromise neuronal function.

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Figure 1: Distribution and localization of oligophrenin-1 in the brain.
Figure 7: Oligophrenin-1 interacts with Homer.
Figure 2: Knock-down of oligophrenin-1 levels using RNAi and antisense RNA technologies.
Figure 3: Oligophrenin-1 siRNAs cause a reduction in spine length in CA1 pyramidal cells in hippocampal slices.
Figure 4: Ophn-1 antisense RNA causes a reduction in spine length in CA1 pyramidal cells in hippocampal slices.
Figure 5: Rho GTPase activation assays and activated Rho GTPase spine phenotypes.
Figure 6: Oligophrenin-1 affects the RhoA/Rho-kinase signaling pathway.

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References

  1. Chelly, J. & Mandel, J.L. Monogenic causes of X-linked mental retardation. Nat. Rev. Genet. 2, 669–680 (2001).

    Article  CAS  Google Scholar 

  2. Frints, S.G., Froyen, G., Marynen, P. & Fryns, J.P. X-linked mental retardation: vanishing boundaries between non-specific (MRX) and syndromic (MRXS) forms. Clin. Genet. 62, 423–432 (2002).

    Article  CAS  Google Scholar 

  3. Ramakers, G.J. Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci. 25, 191–199 (2002).

    Article  CAS  Google Scholar 

  4. Van Aelst, L. & D'Souza-Schorey, C. Rho GTPases and network signaling. Genes Dev. 11, 2295–2322 (1997).

    Article  CAS  Google Scholar 

  5. Luo, L. Rho GTPases in neuronal morphogenesis. Nat. Rev. Neurosci. 1, 173–180 (2000).

    Article  CAS  Google Scholar 

  6. Nakayama, A.Y., Harms, M.B. & Luo, L. Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci. 20, 5329–5338 (2000).

    Article  CAS  Google Scholar 

  7. Tashiro, A., Minden, A. & Yuste, R. Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb. Cortex 10, 927–938 (2000).

    Article  CAS  Google Scholar 

  8. Billuart, P. et al. Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. Nature 392, 923–926 (1998).

    Article  CAS  Google Scholar 

  9. Allen, K.M. et al. PAK3 mutation in nonsyndromic X-linked mental retardation. Nat. Genet. 20, 25–30 (1998).

    Article  CAS  Google Scholar 

  10. Kutsche, K. et al. Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat. Genet. 26, 247–250 (2000).

    Article  CAS  Google Scholar 

  11. Fauchereau, F. et al. The RhoGAP activity of OPHN1, a new F-actin-binding protein is negatively controlled by its amino-terminal domain. Mol. Cell. Neurosci. 23, 574–586 (2003).

    Article  CAS  Google Scholar 

  12. Hering, H. & Sheng, M. Dendritic spines: structure, dynamics and regulation. Nat. Rev. Neurosci. 2, 880–888 (2001).

    Article  CAS  Google Scholar 

  13. Engert, F. & Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999).

    Article  CAS  Google Scholar 

  14. Maletic-Savatic, M., Malinow, R. & Svoboda, K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923–1927 (1999).

    Article  CAS  Google Scholar 

  15. Toni, N., Buchs, P.A., Nikonenko, I., Bron, C.R. & Muller, D. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999).

    Article  CAS  Google Scholar 

  16. Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 4, 1086–1092 (2001).

    Article  CAS  Google Scholar 

  17. Comery, T.A., Stamoudis, C.X., Irwin, S.A. & Greenough, W.T. Increased density of multiple-head dendritic spines on medium-sized spiny neurons of the striatum in rats reared in a complex environment. Neurobiol. Learn. Mem. 66, 93–96 (1996).

    Article  CAS  Google Scholar 

  18. Purpura, D.P. Dendritic spine “dysgenesis” and mental retardation. Science 186, 1126–1128 (1974).

    Article  CAS  Google Scholar 

  19. Kaufmann, W.E. & Moser, H.W. Dendritic anomalies in disorders associated with mental retardation. Cereb. Cortex 10, 981–991 (2000).

    Article  CAS  Google Scholar 

  20. Fiala, J.C., Spacek, J. & Harris, K.M. Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res. Rev. 39, 29–54 (2002).

    Article  Google Scholar 

  21. Harris, K.M. Structure, development, and plasticity of dendritic spines. Curr. Opin. Neurobiol. 9, 343–348 (1999).

    Article  CAS  Google Scholar 

  22. Comery, T.A. et al. Abnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits. Proc. Natl. Acad. Sci. USA 94, 5401–5404 (1997).

    Article  CAS  Google Scholar 

  23. Nimchinsky, E.A., Oberlander, A.M. & Svoboda, K. Abnormal development of dendritic spines in FMR1 knock-out mice. J. Neurosci. 21, 5139–5146 (2001).

    Article  CAS  Google Scholar 

  24. Uehata, M. et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389, 990–994 (1997).

    Article  CAS  Google Scholar 

  25. Amano, M., Fukata, Y. & Kaibuchi, K. Regulation and functions of Rho-associated kinase. Exp. Cell Res. 261, 44–51 (2000).

    Article  CAS  Google Scholar 

  26. Beneken, J. et al. Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition. Neuron 26, 143–154 (2000).

    Article  CAS  Google Scholar 

  27. Fagni, L., Worley, P.F. & Ango, F. Homer as both a scaffold and transduction molecule. Sci. STKE 137, 1–7 (2002).

    Google Scholar 

  28. Xiao, B., Cheng, J. & Worley, P.F. Homer: a link between neural activity and glutamate receptor function. Curr. Opin. Neurobiol. 10, 370–374 (2000).

    Article  CAS  Google Scholar 

  29. Huber, K.M., Gallagher, S.M., Warren, S.T. & Bear, M.F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. USA 99, 7746–7750 (2003).

    Article  Google Scholar 

  30. Billuart, P., Winter, C.G., Maresh, A., Zhao, X. & Luo, L. Regulating axon branch stability: the role of p190 RhoGAP in repressing a retraction signaling pathway. Cell 107, 195–207 (2001).

    Article  CAS  Google Scholar 

  31. Sala, C. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001).

    Article  CAS  Google Scholar 

  32. Sala, C. et al. Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a. J. Neurosci. 23, 6327–6337 (2003).

    Article  CAS  Google Scholar 

  33. Fischer, M., Kaech, S., Wagner, U., Brinkhaus, H. & Matus, A. Glutamate receptors regulate actin-based plasticity in dendritic spines. Nat. Neurosci. 3, 887–894 (2000).

    Article  CAS  Google Scholar 

  34. Star, E.N., Kwiatkowski, D.J. & Murthy, V.N. Rapid turnover of actin in dendritic spines and its regulation by activity. Nat. Neurosci. 5, 239–246 (2002).

    Article  CAS  Google Scholar 

  35. Ackermann, M. & Matus, A. Activity-induced targeting of profilin and stabilization of dendritic spine morphology. Nat. Neurosci. 6, 1194–1200 (2003).

    Article  CAS  Google Scholar 

  36. McKinney, R.A., Capogna, M., Dürr, R., Gähwiler, B.H. & Thompson, S.M. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat. Neurosci. 2, 44–49 (1999).

    Article  CAS  Google Scholar 

  37. Sin, W.C., Haas, K., Ruthazer, E.S. & Cline, H.T. Dendrite growth increased by visual activity requires NMDA receptor and Rho GTPases. Nature 419, 475–480 (2002).

    Article  CAS  Google Scholar 

  38. Yuan, J.P. et al. Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell 114, 777–789 (2003).

    Article  CAS  Google Scholar 

  39. Korkotian, E. & Segal, M. Release of calcium from stores alters the morphology of dendritic spines in cultured hippocampal neurons. Proc. Natl. Acad. Sci. USA 96, 12068–12072 (1999).

    Article  CAS  Google Scholar 

  40. Hayashi, K. et al. Modulatory role of Drebrin on the cytoskeleton within dendritic spines in the rat cerebral cortex. J. Neurosci. 16, 7161–7170 (1996).

    Article  CAS  Google Scholar 

  41. Majewska, A., Tashiro, A. & Yuste, R. Regulation of spine calcium dynamics by rapid spine motility. J. Neurosci. 20, 8262–8268 (2000).

    Article  CAS  Google Scholar 

  42. Yuste, R., Majewska, A. & Holthoff, K. From form to function: calcium compartmentalization in dendritic spines. Nat. Neurosci. 3, 653–659 (2000).

    Article  CAS  Google Scholar 

  43. Bergmann, C. et al. Oligophrenin-1 (OPHN1) gene mutation causes X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain 126, 1537–1544 (2003).

    Article  Google Scholar 

  44. Philip, N. et al. Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia. J. Med. Genet. 40, 441–446 (2003).

    Article  CAS  Google Scholar 

  45. Joneson, T., McDonough, M., Bar-Sagi, D. & Van Aelst, L. RAC regulation of actin polymerization and proliferation by a pathway distinct from Jun kinase. Science 274, 1374–1376 (1996).

    Article  CAS  Google Scholar 

  46. Pak, D.T., Yang, S., Rudolph-Correia, S., Kim, E. & Sheng, M. Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron 31, 289–303 (2001).

    Article  CAS  Google Scholar 

  47. Stoppini, L., Buchs, P.A. & Muller, D. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173–182 (1991).

    Article  CAS  Google Scholar 

  48. Yamaguchi, Y., Katoh, H., Yasui, H., Mori, K. & Negishi, M. RhoA inhibits the nerve growth factor-induced Rac1 activation through Rho-associated kinase-dependent pathway. J. Biol. Chem. 276, 18977–18983 (2001).

    Article  CAS  Google Scholar 

  49. Lau, L.F. et al. Interaction of the N-methyl-D-aspartate receptor complex with a novel synapse-associated protein, SAP102. J. Biol. Chem. 271, 21622–21628 (1996).

    Article  CAS  Google Scholar 

  50. Cho, K.O., Hunt, C.A. & Kennedy, M.B. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein. Neuron 9, 929–942 (1992).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank A. Piccini, E. Ruthazer, B. Burbach, C. Kopec, K. Jensen and H. Hsieh for technical assistance. We also thank H. Cline, R. Malinow, J. Skowronski, K. Svoboda, J. Rodriguez and members of the Van Aelst Laboratory for discussions and/or critical reading of the manuscript. This work was supported by the National Institutes of Health and Dana Foundation (to L.V.A.), the Wellcome Trust (to S.E.N. and C.J.A.) and the National Institutes of Health (to E.E.G).

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  1. Eve-Ellen Govek and Sarah E Newey: These authors contributed equally to this work.

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, 11724, New York, USA

    Eve-Ellen Govek, Sarah E Newey, Colin J Akerman, Justin R Cross, Lieven Van der Veken & Linda Van Aelst

  2. Molecular and Cellular Biology Program, State University of New York at Stony Brook, Stony Brook, 11794, New York, USA

    Eve-Ellen Govek & Linda Van Aelst

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Supplementary information

Supplementary Fig. 1

Typical biolistic transfection and morphology of a hippocampal slice. The left panel is a fluorescence image to show the transfected GFP-expressing cells, while the right panel shows the morphology of a hippocampal slice. Indicated are the CA1, CA3, and dentate gyrus (DG) regions, as well as glial cells (glia). In the hippocampal slice, axons from CA3 pyramidal neurons synapse onto dendritic spines of CA1 pyramidal neurons. Three GFP expressing cells can be observed in the CA1 and CA3 regions; this is the average number of transfected cells in a typical imaging experiment. Only cells from the CA1 region were imaged and analyzed. The very low transfection rate in these slices (estimated 0.1%), and the very small number of synapses likely to be made on a transfected CA1 cell by a transfected CA3 cell in this system (< 1%), strongly suggest that the effect of reduced oligophrenin-1 levels on spine morphology are due to a post-synaptic role for oligophrenin-1. Scale bar, 250 µm. (JPG 44 kb)

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Govek, EE., Newey, S., Akerman, C. et al. The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nat Neurosci 7, 364–372 (2004). https://doi.org/10.1038/nn1210

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