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Gene Review

Ntn1  -  netrin 1

Mus musculus

Synonyms: AI561871, BC019633, Netrin-1
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Disease relevance of Ntn1


High impact information on Ntn1

  • In the embryonic spinal cord, the floor plate chemoattractant Netrin-1 is required to guide commissural neuron axons to the midline [2].
  • 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 [3].
  • A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion [3].
  • Defects in several forebrain commissures are also observed, suggesting additional guidance roles for netrin-1 [4].
  • Thus, activation of MAPK signalling through Dcc contributes to netrin signalling in axon growth and guidance [5].

Chemical compound and disease context of Ntn1


Biological context of Ntn1

  • Loss-of-function mutations in Slit2 and Robo1 yield similar phenotypes, characterized by disorganized end buds (EBs) reminiscent of those present in Ntn1(-/-) glands, suggesting that SLIT2 and NTN1 function in concert during mammary development [8].
  • Here we extend these studies to show that cVNN trajectories and LHRH cell migration in netrin 1 (Ntn1) mutant mice are also abnormal [9].
  • Inactivation of the murine Dcc gene caused defects in axonal projections that are similar to those observed in netrin-1-deficient mice but did not affect growth, differentiation, morphogenesis or tumorigenesis in mouse intestine [10].
  • The netrin family of axon guidance cues has been shown to play a pivotal role in the guidance of a variety of axon projections during embryonic development, both in the vertebrate and invertebrate [11].
  • Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance [12].

Anatomical context of Ntn1

  • Substantially reduced numbers of LHRH neurons are found in the basal forebrain and many LHRH neurons migrate into the cerebral cortex of Ntn1 knockout mice [9].
  • These results are consistent with the idea that the chemoattraction of DCC+ vomeronasal axons by a gradient of netrin 1 protein in the ventral forebrain guides the cVNN, which, in turn, determines the direction of LHRH neuron migration in the forebrain [9].
  • Postnatal day 0 netrin 1 mutant mice also demonstrate corticospinal tract abnormalities [13].
  • Thus, we demonstrate that Netrin-1 is a secreted neural guidance cue with the unique ability to attract both blood vessels and axons, and suggest that other cues may also function as vascular endothelial growth factors [14].
  • In addition, in the presence of netrin 1, the migrating neurons are not isolated but are associated with thick fascicles of neurites, typical of the neurophilic way of migration [15].

Associations of Ntn1 with chemical compounds

  • The netrin 1 receptor DCC and its Caenorhabditis elegans homolog UNC-40 have been implicated in directing the guidance of axons toward netrin sources, whereas the C. elegans UNC-6 receptor, UNC-5 is necessary for migrations away from UNC-6 [13].
  • Here, we characterize a new member of the family, beta-netrin. beta-Netrin is homologous to the NH(2) terminus of laminin chain short arms; it contains a laminin-like domain VI and 3.5 laminin EGF repeats and a netrin C domain [16].
  • Finally, optical recordings with the Ca(2+) indicator Fura 2-AM show that spontaneous neuronal activity is reduced in the septum of netrin 1-mutant mice [17].
  • We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1 [12].
  • The unique distribution of DCC-immunoreactivity in adult ventral midbrain dopamine neurons suggests that netrin-1/DCC signaling could function in plasticity and remodeling previously identified in dopamine projection pathways [7].

Physical interactions of Ntn1


Regulatory relationships of Ntn1


Other interactions of Ntn1

  • Loss of function through a genetic deletion in either Dcc or Ntn1 results in the migration of many LHRH neurons to inappropriate destinations [9].
  • Unc5h3 encodes a receptor mediating the repulsive action for Netrin-1 and has an important role during cell migration in the developing murine cerebellum [21].
  • We report the identification of a second mouse netrin gene, which we name netrin-3 [22].
  • Specifically, we find that Gli2 is required for the initial extension of axons from SACMN cell bodies, and that netrin-1 and its receptor Dcc are required for the proper dorsal migration of these cells and the dorsally directed extension of SACMN axons toward the LEPs [23].
  • MAP1B is required for Netrin 1 signaling in neuronal migration and axonal guidance [24].
  • Netrin 1 binding to Dcc on mature oligodendrocytes recruits Fyn to a complex with the Dcc intracellular domain that includes FAK and N-WASP, resulting in the inhibition of RhoA and inducing process remodeling [25].

Analytical, diagnostic and therapeutic context of Ntn1

  • Netrin-1 mRNA is detected in these target tissues by in situ hybridization, and both netrin-1 protein and heterologous cells secreting netrin-1 can mimic the outgrowth-promoting effect of these target tissues in vitro [26].
  • Furthermore, the growth of corticofugal axons is oriented toward an ectopic source of netrin-1 in vitro, and a function blocking anti-netrin-1 antiserum specifically abolishes the cortical axon outgrowth elicited by explants of lateral GE and the ISS in collagen gel cocultures [26].


  1. Cloning of three mouse Unc5 genes and their expression patterns at mid-gestation. Engelkamp, D. Mech. Dev. (2002) [Pubmed]
  2. The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Charron, F., Stein, E., Jeong, J., McMahon, A.P., Tessier-Lavigne, M. Cell (2003) [Pubmed]
  3. 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]
  4. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Serafini, T., Colamarino, S.A., Leonardo, E.D., Wang, H., Beddington, R., Skarnes, W.C., Tessier-Lavigne, M. Cell (1996) [Pubmed]
  5. 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]
  6. Netrin-1 and DCC mediate axon guidance locally at the optic disc: loss of function leads to optic nerve hypoplasia. Deiner, M.S., Kennedy, T.E., Fazeli, A., Serafini, T., Tessier-Lavigne, M., Sretavan, D.W. Neuron (1997) [Pubmed]
  7. Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents. Osborne, P.B., Halliday, G.M., Cooper, H.M., Keast, J.R. Neuroscience (2005) [Pubmed]
  8. Slit2 and netrin 1 act synergistically as adhesive cues to generate tubular bi-layers during ductal morphogenesis. Strickland, P., Shin, G.C., Plump, A., Tessier-Lavigne, M., Hinck, L. Development (2006) [Pubmed]
  9. Netrin 1-mediated chemoattraction regulates the migratory pathway of LHRH neurons. Schwarting, G.A., Raitcheva, D., Bless, E.P., Ackerman, S.L., Tobet, S. Eur. J. Neurosci. (2004) [Pubmed]
  10. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Fazeli, A., Dickinson, S.L., Hermiston, M.L., Tighe, R.V., Steen, R.G., Small, C.G., Stoeckli, E.T., Keino-Masu, K., Masu, M., Rayburn, H., Simons, J., Bronson, R.T., Gordon, J.I., Tessier-Lavigne, M., Weinberg, R.A. Nature (1997) [Pubmed]
  11. Netrin-3 protein is localized to the axons of motor, sensory, and sympathetic neurons. Seaman, C., Cooper, H.M. Mech. Dev. (2001) [Pubmed]
  12. Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance. Meriane, M., Tcherkezian, J., Webber, C.A., Danek, E.I., Triki, I., McFarlane, S., Bloch-Gallego, E., Lamarche-Vane, N. J. Cell Biol. (2004) [Pubmed]
  13. The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons. Finger, J.H., Bronson, R.T., Harris, B., Johnson, K., Przyborski, S.A., Ackerman, S.L. J. Neurosci. (2002) [Pubmed]
  14. The axonal attractant Netrin-1 is an angiogenic factor. Park, K.W., Crouse, D., Lee, M., Karnik, S.K., Sorensen, L.K., Murphy, K.J., Kuo, C.J., Li, D.Y. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  15. Netrin 1 acts as an attractive or as a repulsive cue for distinct migrating neurons during the development of the cerebellar system. Alcántara, S., Ruiz, M., De Castro, F., Soriano, E., Sotelo, C. Development (2000) [Pubmed]
  16. A novel member of the netrin family, beta-netrin, shares homology with the beta chain of laminin: identification, expression, and functional characterization. Koch, M., Murrell, J.R., Hunter, D.D., Olson, P.F., Jin, W., Keene, D.R., Brunken, W.J., Burgeson, R.E. J. Cell Biol. (2000) [Pubmed]
  17. Aberrant development of hippocampal circuits and altered neural activity in netrin 1-deficient mice. Barallobre, M.J., Del Río, J.A., Alcántara, S., Borrell, V., Aguado, F., Ruiz, M., Carmona, M.A., Martín, M., Fabre, M., Yuste, R., Tessier-Lavigne, M., Soriano, E. Development (2000) [Pubmed]
  18. Divergent properties of mouse netrins. PuschelPüschel, A.W. Mech. Dev. (1999) [Pubmed]
  19. Netrin 1 regulates ventral tangential migration of guidepost neurons in the lateral olfactory tract. Kawasaki, T., Ito, K., Hirata, T. Development (2006) [Pubmed]
  20. Netrin stimulates tyrosine phosphorylation of the UNC-5 family of netrin receptors and induces Shp2 binding to the RCM cytodomain. Tong, J., Killeen, M., Steven, R., Binns, K.L., Culotti, J., Pawson, T. J. Biol. Chem. (2001) [Pubmed]
  21. Rat neurological mutations cerebellar vermis defect and hobble are caused by mutations in the netrin-1 receptor gene Unc5h3. Kuramoto, T., Kuwamura, M., Serikawa, T. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  22. Netrin-3, a mouse homolog of human NTN2L, is highly expressed in sensory ganglia and shows differential binding to netrin receptors. Wang, H., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Tessier-Lavigne, M. J. Neurosci. (1999) [Pubmed]
  23. Molecular control of spinal accessory motor neuron/axon development in the mouse spinal cord. Dillon, A.K., Fujita, S.C., Matise, M.P., Jarjour, A.A., Kennedy, T.E., Kollmus, H., Arnold, H.H., Weiner, J.A., Sanes, J.R., Kaprielian, Z. J. Neurosci. (2005) [Pubmed]
  24. MAP1B is required for Netrin 1 signaling in neuronal migration and axonal guidance. Del Río, J.A., González-Billault, C., Ureña, J.M., Jiménez, E.M., Barallobre, M.J., Pascual, M., Pujadas, L., Simó, S., La Torre, A., Wandosell, F., Avila, J., Soriano, E. Curr. Biol. (2004) [Pubmed]
  25. Netrin 1 and Dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA. Rajasekharan, S., Baker, K.A., Horn, K.E., Jarjour, A.A., Antel, J.P., Kennedy, T.E. Development (2009) [Pubmed]
  26. A role for netrin-1 in the guidance of cortical efferents. Métin, C., Deléglise, D., Serafini, T., Kennedy, T.E., Tessier-Lavigne, M. Development (1997) [Pubmed]
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