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Chemical Compound Review

Netrin     2-diethylaminoethyl 1-(3,4...

Synonyms: CHEMBL2106860, LS-57937, AC1L3SZ1, C20H31NO2.HCl, 1950-31-8, ...
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Disease relevance of G 3012


High impact information on G 3012

  • Netrin receptors of the Deleted in Colorectal Cancer (DCC) family are implicated in attraction and those of the UNC5 family in repulsion, but genetic evidence also suggests involvement of the DCC protein UNC-40 in some cases of repulsion [5].
  • A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion [5].
  • Deleted in Colorectal Cancer (DCC) encodes a netrin receptor [6].
  • UNC-6 netrin, a laminin-related protein secreted from neuroglia and neurons along the ventral midline, orients migrating cells and pioneering growth cones on the nematode epidermis [1].
  • The phenotypes strongly resemble those of a deletion of the two Drosophila Netrin genes [7].

Biological context of G 3012

  • Moreover, Frazzled itself is actively localized within the axon through its cytoplasmic domain, and thereby rearranges Netrin protein into a spatial pattern completely different from the pattern of Netrin gene expression [8].
  • In Caenorhabditis elegans, cell migration is guided by localized cues, including molecules such as EGL-17/FGF and UNC-6/netrin [9].
  • Blockers of Src family kinases inhibited FAK phosphorylation and axon outgrowth and attraction by netrin [10].
  • Here we report that the netrin receptor DCC (deleted in colorectal cancer) interacts with the focal adhesion kinase (FAK), a kinase implicated in regulating cell adhesion and migration [11].
  • Both Netrin genes map close to each other on the X chromosome, and embryos deficient for this region exhibit defects in commissure formation [12].

Anatomical context of G 3012

  • These results show that netrin-1 is a chemotropic factor expressed by floor plate cells and suggest that the two netrin proteins guide commissural axons in the developing spinal cord [13].
  • Frazzled-dependent guidance of one pioneer neuron in the central nervous system can be accounted for solely on the basis of this ability of Frazzled to control Netrin distribution, and not by Frazzled signalling [8].
  • Here we report that, in Xenopus, laminin-1 from the extracellular matrix (ECM), converts netrin-mediated attraction into repulsion [14].
  • The paper presents strong evidence that pancreatic epithelial cells adhere, spread and migrate on netrin-coated substrata through alpha6beta4 [15].
  • Consistent with a role in pancreatic development in vivo, netrin is expressed together with these integrins in fetal pancreatic epithelium [15].

Associations of G 3012 with other chemical compounds

  • Low levels of cyclic AMP in growth cones also lead to the conversion of netrin-induced attraction into repulsion, and we show that the amount of cAMP decreases in the presence of laminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect [14].
  • Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction [16].
  • Our data demonstrated that glucose-induced aging in vitro caused an elongation and thickening of cell processes and significantly increased the expression of netrin reflecting a more mature state of oligodendrocyte development [17].

Gene context of G 3012

  • Inhibition of ERK-1/2 antagonizes netrin-dependent axon outgrowth and orientation [18].
  • The unc-129 gene, like the unc-6 netrin gene, is required to guide pioneer motoraxons along the dorsoventral axis of Caenorhabditis elegans. unc-129 encodes a member of the transforming growth factor-beta (TGF-beta) superfamily of secreted signaling molecules and is expressed in dorsal, but not ventral, rows of body wall muscles [19].
  • These genes provide insights into glial biology: we show unc-5 (a repulsive netrin receptor) orients glial migrations and the draper gene mediates glial engulfment of apoptotic neurons and larval locomotion [20].
  • In the src-1 mutant, the expression of unc-5/netrin receptor is normally regulated, and neither the precocious expression of UNC-5 nor the mutation in the unc-5 gene significantly affects the DTC migration defect [21].
  • Mutations in Abl and trio dominantly enhance fra and Netrin mutant CNS phenotypes, and fra;Abl and fra;trio double mutants display a dramatic loss of axons in a majority of commissures [22].

Analytical, diagnostic and therapeutic context of G 3012


  1. UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. Chan, S.S., Zheng, H., Su, M.W., Wilk, R., Killeen, M.T., Hedgecock, E.M., Culotti, J.G. Cell (1996) [Pubmed]
  2. The Netrin receptor Neogenin is required for neural tube formation and somitogenesis in zebrafish. Mawdsley, D.J., Cooper, H.M., Hogan, B.M., Cody, S.H., Lieschke, G.J., Heath, J.K. Dev. Biol. (2004) [Pubmed]
  3. The NTN2L gene encoding a novel human netrin maps to the autosomal dominant polycystic kidney disease region on chromosome 16p13.3. Van Raay, T.J., Foskett, S.M., Connors, T.D., Klinger, K.W., Landes, G.M., Burn, T.C. Genomics (1997) [Pubmed]
  4. Survival trees for analyzing clinical outcome in lung adenocarcinomas based on gene expression profiles: identification of neogenin and diacylglycerol kinase alpha expression as critical factors. Berrar, D., Sturgeon, B., Bradbury, I., Downes, C.S., Dubitzky, W. J. Comput. Biol. (2005) [Pubmed]
  5. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Hong, K., Hinck, L., Nishiyama, M., Poo, M.M., Tessier-Lavigne, M., Stein, E. Cell (1999) [Pubmed]
  6. Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Keino-Masu, K., Masu, M., Hinck, L., Leonardo, E.D., Chan, S.S., Culotti, J.G., Tessier-Lavigne, M. Cell (1996) [Pubmed]
  7. frazzled encodes a Drosophila member of the DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. Kolodziej, P.A., Timpe, L.C., Mitchell, K.J., Fried, S.R., Goodman, C.S., Jan, L.Y., Jan, Y.N. Cell (1996) [Pubmed]
  8. The Drosophila Netrin receptor Frazzled guides axons by controlling Netrin distribution. Hiramoto, M., Hiromi, Y., Giniger, E., Hotta, Y. Nature (2000) [Pubmed]
  9. Control of cell migration during Caenorhabditis elegans development. Blelloch, R., Newman, C., Kimble, J. Curr. Opin. Cell Biol. (1999) [Pubmed]
  10. Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction. Liu, G., Beggs, H., Jürgensen, C., Park, H.T., Tang, H., Gorski, J., Jones, K.R., Reichardt, L.F., Wu, J., Rao, Y. Nat. Neurosci. (2004) [Pubmed]
  11. Focal adhesion kinase in netrin-1 signaling. Ren, X.R., Ming, G.L., Xie, Y., Hong, Y., Sun, D.M., Zhao, Z.Q., Feng, Z., Wang, Q., Shim, S., Chen, Z.F., Song, H.J., Mei, L., Xiong, W.C. Nat. Neurosci. (2004) [Pubmed]
  12. Guidance cues at the Drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs. Harris, R., Sabatelli, L.M., Seeger, M.A. Neuron (1996) [Pubmed]
  13. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Kennedy, T.E., Serafini, T., de la Torre, J.R., Tessier-Lavigne, M. Cell (1994) [Pubmed]
  14. Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Höpker, V.H., Shewan, D., Tessier-Lavigne, M., Poo, M., Holt, C. Nature (1999) [Pubmed]
  15. Brain meets pancreas: netrin, an axon guidance molecule, controls epithelial cell migration. Hebrok, M., Reichardt, L.F. Trends Cell Biol. (2004) [Pubmed]
  16. Activation of FAK and Src are receptor-proximal events required for netrin signaling. Li, W., Lee, J., Vikis, H.G., Lee, S.H., Liu, G., Aurandt, J., Shen, T.L., Fearon, E.R., Guan, J.L., Han, M., Rao, Y., Hong, K., Guan, K.L. Nat. Neurosci. (2004) [Pubmed]
  17. Exogenous application of glucose induces aging in rat cerebral oligodendrocytes as revealed by alteration in telomere length. Dabouras, V., Rothermel, A., Reininger-Mack, A., Wien, S.L., Layer, P.G., Robitzki, A.A. Neurosci. Lett. (2004) [Pubmed]
  18. Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation. Forcet, C., Stein, E., Pays, L., Corset, V., Llambi, F., Tessier-Lavigne, M., Mehlen, P. Nature (2002) [Pubmed]
  19. Pioneer axon guidance by UNC-129, a C. elegans TGF-beta. Colavita, A., Krishna, S., Zheng, H., Padgett, R.W., Culotti, J.G. Science (1998) [Pubmed]
  20. Unwrapping glial biology: Gcm target genes regulating glial development, diversification, and function. Freeman, M.R., Delrow, J., Kim, J., Johnson, E., Doe, C.Q. Neuron (2003) [Pubmed]
  21. SRC-1, a non-receptor type of protein tyrosine kinase, controls the direction of cell and growth cone migration in C. elegans. Itoh, B., Hirose, T., Takata, N., Nishiwaki, K., Koga, M., Ohshima, Y., Okada, M. Development (2005) [Pubmed]
  22. The Abelson tyrosine kinase, the Trio GEF and Enabled interact with the Netrin receptor Frazzled in Drosophila. Forsthoefel, D.J., Liebl, E.C., Kolodziej, P.A., Seeger, M.A. Development (2005) [Pubmed]
  23. Lesion-induced regulation of netrin receptors and modification of netrin-1 expression in the retina of fish and grafted rats. Petrausch, B., Jung, M., Leppert, C.A., Stuermer, C.A. Mol. Cell. Neurosci. (2000) [Pubmed]
  24. Developmental shift in expression of netrin receptors in the rat spinal cord: predominance of UNC-5 homologues in adulthood. Manitt, C., Thompson, K.M., Kennedy, T.E. J. Neurosci. Res. (2004) [Pubmed]
  25. Expression of netrin-1 and its receptors DCC and UNC-5H2 after axotomy and during regeneration of adult rat retinal ganglion cells. Ellezam, B., Selles-Navarro, I., Manitt, C., Kennedy, T.E., McKerracher, L. Exp. Neurol. (2001) [Pubmed]
  26. An amphioxus netrin gene is expressed in midline structures during embryonic and larval development. Shimeld, S. Dev. Genes Evol. (2000) [Pubmed]
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