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UNC-6 and UNC-40 promote dendritic growth through PAR-4 in Caenorhabditis elegans neurons

Nature Neuroscience volume 14, pages 165–172 (2011)Cite this article

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Abstract

Axons navigating through the developing nervous system are instructed by external attractive and repulsive cues. Emerging evidence suggests the same cues control dendrite development, but it is not understood how they differentially instruct axons and dendrites. We studied a C. elegans motor neuron whose axon and dendrite adopt different trajectories and lengths. We found that the guidance cue UNC-6 (Netrin) is required for both axon and dendrite development. Its repulsive receptor UNC-5 repelled the axon from the ventral cell body, whereas the attractive receptor UNC-40 (DCC) was dendritically enriched and promotes antero-posterior dendritic growth. Although the endogenous ventrally secreted UNC-6 instructs axon guidance, dorsal or even membrane-tethered UNC-6 could support dendrite development. Unexpectedly, the serine-threonine kinase PAR-4 (LKB1) was selectively required for the activity of the UNC-40 pathway in dendrite outgrowth. These data suggest that axon and dendrite of one neuron interpret common environmental cues with different receptors and downstream signaling pathways.

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Figure 1: Development of the DA9 motor neuron in wild-type C. elegans.
Figure 2: UNC-6 (Netrin) regulates dendrite outgrowth through UNC-40 (DCC).
Figure 3: UNC-40 is necessary and sufficient for dendrite outgrowth.
Figure 4: Local, non-graded UNC-6 signaling is sufficient for dendrite outgrowth.
Figure 5: PAR-4 (LKB1) is necessary and sufficient for dendrite outgrowth.
Figure 6: PAR-4 acts downstream of UNC-6 and UNC-40.
Figure 7: unc-34 and par-4 act in parallel in AVM development.

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References

  1. Polleux, F., Morrow, T. & Ghosh, A. Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature 404, 567–573 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Komiyama, T., Sweeney, L.B., Schuldiner, O., Garcia, K.C. & Luo, L. Graded expression of semaphorin-1a cell-autonomously directs dendritic targeting of olfactory projection neurons. Cell 128, 399–410 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Hedgecock, E.M., Culotti, J.G. & Hall, D.H. The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4, 61–85 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Kidd, T., Bland, K.S. & Goodman, C.S. Slit is the midline repellent for the robo receptor in Drosophila. Cell 96, 785–794 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Suli, A., Mortimer, N., Shepherd, I. & Chien, C.B. Netrin/DCC signaling controls contralateral dendrites of octavolateralis efferent neurons. J. Neurosci. 26, 13328–13337 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Furrer, M.P., Kim, S., Wolf, B. & Chiba, A. Robo and Frazzled/DCC mediate dendritic guidance at the CNS midline. Nat. Neurosci. 6, 223–230 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Furrer, M.P., Vasenkova, I., Kamiyama, D., Rosado, Y. & Chiba, A. Slit and Robo control the development of dendrites in Drosophila CNS. Development 134, 3795–3804 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Finger, J.H. et al. The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons. J. Neurosci. 22, 10346–10356 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Serafini, T. et al. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78, 409–424 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Serafini, T. et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001–1014 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Gertler, F.B. et al. enabled, a dosage-sensitive suppressor of mutations in the Drosophila Abl tyrosine kinase, encodes an Abl substrate with SH3 domain-binding properties. Genes Dev. 9, 521–533 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Yu, T.W., Hao, J.C., Lim, W., Tessier-Lavigne, M. & Bargmann, C.I. Shared receptors in axon guidance: SAX-3/Robo signals via UNC-34/Enabled and a Netrin-independent UNC-40/DCC function. Nat. Neurosci. 5, 1147–1154 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Gitai, Z., Yu, T.W., Lundquist, E.A., Tessier-Lavigne, M. & Bargmann, C.I. The netrin receptor UNC-40/DCC stimulates axon attraction and outgrowth through enabled and, in parallel, Rac and UNC-115/AbLIM. Neuron 37, 53–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Ming, G. et al. Phospholipase C-gamma and phosphoinositide 3-kinase mediate cytoplasmic signaling in nerve growth cone guidance. Neuron 23, 139–148 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, G. et al. Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction. Nat. Neurosci. 7, 1222–1232 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhu, X.J. et al. Myosin X regulates netrin receptors and functions in axonal path-finding. Nat. Cell Biol. 9, 184–192 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Li, X. et al. Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling. Nat. Neurosci. 11, 28–35 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Liu, G. et al. p130CAS is required for netrin signaling and commissural axon guidance. J. Neurosci. 27, 957–968 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  21. White, J.G., Southgate, E., Thomson, J.N. & Brenner, S. The structure of the nervous system of the nematode Caenorhabditis elegans. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 314, 1–340 (1986).

    Article  CAS  Google Scholar 

  22. Sym, M., Robinson, N. & Kenyon, C. MIG-13 positions migrating cells along the anteroposterior body axis of C. elegans. Cell 98, 25–36 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Klassen, M.P. & Shen, K. Wnt signaling positions neuromuscular connectivity by inhibiting synapse formation in C. elegans. Cell 130, 704–716 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Wadsworth, W.G. Moving around in a worm: netrin UNC-6 and circumferential axon guidance in C. elegans. Trends Neurosci. 25, 423–429 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Wadsworth, W.G., Bhatt, H. & Hedgecock, E.M. Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans. Neuron 16, 35–46 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Hamelin, M., Zhou, Y., Su, M.W., Scott, I.M. & Culotti, J.G. Expression of the UNC-5 guidance receptor in the touch neurons of C. elegans steers their axons dorsally. Nature 364, 327–330 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Poon, V.Y., Klassen, M.P. & Shen, K. UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites. Nature 455, 669–673 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Colón-Ramos, D.A., Margeta, M.A. & Shen, K. Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans. Science 318, 103–106 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhou, P. et al. Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55, 53–68 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brankatschk, M. & Dickson, B.J. Netrins guide Drosophila commissural axons at short range. Nat. Neurosci. 9, 188–194 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Moore, S.W., Biais, N. & Sheetz, M.P. Traction on immobilized netrin-1 is sufficient to reorient axons. Science 325, 166 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Watts, J.L., Morton, D.G., Bestman, J. & Kemphues, K.J. The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry. Development 127, 1467–1475 (2000).

    CAS  PubMed  Google Scholar 

  33. Barnes, A.P. et al. LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell 129, 549–563 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Kemphues, K.J., Priess, J.R., Morton, D.G. & Cheng, N.S. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Tenlen, J.R., Molk, J.N., London, N., Page, B.D. & Priess, J.R. MEX-5 asymmetry in one-cell C. elegans embryos requires PAR-4- and PAR-1-dependent phosphorylation. Development 135, 3665–3675 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Shelly, M., Cancedda, L., Heilshorn, S., Sumbre, G. & Poo, M.M. LKB1/STRAD promotes axon initiation during neuronal polarization. Cell 129, 565–577 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Kolodziej, P.A. et al. frazzled encodes a Drosophila member of the DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. Cell 87, 197–204 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Chan, S.S. et al. UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 87, 187–195 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Lim, Y.S., Mallapur, S., Kao, G., Ren, X.C. & Wadsworth, W.G. Netrin UNC-6 and the regulation of branching and extension of motoneuron axons from the ventral nerve cord of Caenorhabditis elegans. J. Neurosci. 19, 7048–7056 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hagedorn, E.J. et al. Integrin acts upstream of netrin signaling to regulate formation of the anchor cell's invasive membrane in C. elegans. Dev. Cell 17, 187–198 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Margeta, M.A., Wang, G.J. & Shen, K. Clathrin adaptor AP-1 complex excludes multiple postsynaptic receptors from axons in C. elegans. Proc. Natl. Acad. Sci. USA 106, 1632–1637 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Suzuki, A. & Ohno, S. The PAR-aPKC system: lessons in polarity. J. Cell Sci. 119, 979–987 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Morton, D.G., Roos, J.M. & Kemphues, K.J. par-4, a gene required for cytoplasmic localization and determination of specific cell types in Caenorhabditis elegans embryogenesis. Genetics 130, 771–790 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Martin, S.G. & St Johnston, D. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature 421, 379–384 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Asada, N., Sanada, K. & Fukada, Y. LKB1 regulates neuronal migration and neuronal differentiation in the developing neocortex through centrosomal positioning. J. Neurosci. 27, 11769–11775 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Polleux, F., Giger, R.J., Ginty, D.D., Kolodkin, A.L. & Ghosh, A. Patterning of cortical efferent projections by semaphorin-neuropilin interactions. Science 282, 1904–1906 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Fire, A., Kondo, K. & Waterston, R. Vectors for low copy transformation of C. elegans. Nucleic Acids Res. 18, 4269–4270 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mello, C. & Fire, A. DNA transformation. Methods Cell Biol. 48, 451–482 (1995).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the International Caenorhabditis Genetic Center and the C. Kenyon (University of California, San Francisco), E. Lundquist (University of Kansas) and C. Bargmann (Rockefeller University) laboratories for strains and K. Kemphues laboratory (Cornell University) for par-4 cDNA, as well as C. Gao and Y. Fu for technical assistance. This work was supported by the Human Frontier Science Foundation, the W. M. Keck Foundation and the Howard Hughes Medical Institute (K.S.) and a Boehringer Ingelheim graduate fellowship (H.M.T.).

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  1. Department of Biology, Howard Hughes Medical Institute, Stanford University, California, USA

    Hannah M Teichmann & Kang Shen

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H.M.T. performed all experiments. H.M.T. and K.S. designed and analyzed the experiments and wrote the manuscript.

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Correspondence to Kang Shen.

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Teichmann, H., Shen, K. UNC-6 and UNC-40 promote dendritic growth through PAR-4 in Caenorhabditis elegans neurons. Nat Neurosci 14, 165–172 (2011). https://doi.org/10.1038/nn.2717

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