Netrin 1 Explained

Netrin-1 is a protein that in humans is encoded by the NTN1 gene.^{[1] [2]}

Netrin is included in a family of laminin-related secreted proteins. The function of this gene has not yet been defined; however, netrin is thought to be involved in axon guidance and cell migration during development. Mutations and loss of expression of netrin suggest that variation in netrin may be involved in cancer development.^[2]

Interactions

NTN1 has been shown to interact with Deleted in Colorectal Cancer,^[3] and components of the extracellular matrix and the tumor microenvironment.^[4]

Midline Crossing of Commissural Axons

During the development of the central nervous system, when the dorsal and ventral signaling is being established, the floor plate is an important site for crossing for groups of neural processes at the dorsal midline. Once crossed through the floor plate, these groups are now referred to as commissural axons. These neuronal cell bodies are signaled by Netrin 1 to be attracted to the floor plate from the dorsal half of the neural tube. NTN1 is a gene that encodes for the protein, Netrin-1. In a study done in knockout mice with a depletion of floor plate Netrin-1, it was shown that corticospinal axon tract midline crossing was disrupted.^[5] This study was done to show characteristics of patients with human congenital mirror movement disorder.

Afterwards, proper positioning of axons and midline crossing are pioneered by the Slit-Robo system where Slit proteins act as axonal repellents and Robo proteins (Robo-1, Robo-2, Robo-3) act in conjunction with Slit ligands to be their receptors.^[6] Slit with Robo-1 and Robo-2 repel axonal extension at the midline thereby commissural axons expressing Robo-3 cross the midline by interfering with Slit/Robo-1, Robo-2 repulsive activity. After crossing the floor plate, Robo-3 is downregulated and Slit/Robo-1, Robo-2 continue to express their repulsiveness at the midline. Furthermore, mutations in Robo-3 cause horizontal gaze palsy with progressive scoliosis.

Further reading

• Bouhidel JO, Wang P, Siu KL, Li H, Youn JY, Cai H . Netrin-1 improves post-injury cardiac function in vivo via DCC/NO-dependent preservation of mitochondrial integrity, while attenuating autophagy . Biochim. Biophys. Acta . 1852 . 2 . 277–89 . February 2015 . 24928309 . 4262720 . 10.1016/j.bbadis.2014.06.005 .
• Arakawa H . Netrin-1 and its receptors in tumorigenesis. . Nat. Rev. Cancer . 4 . 12 . 978–87 . 2005 . 15573119 . 10.1038/nrc1504 . 867903 .
• Mehlen P, Furne C . Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis. . Cell. Mol. Life Sci. . 62 . 22 . 2599–616 . 2006 . 16158190 . 10.1007/s00018-005-5191-3 . 29781275 . 11139161 .
• Keino-Masu K, Masu M, Hinck L, etal . Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. . Cell . 87 . 2 . 175–85 . 1996 . 8861902 . 10.1016/S0092-8674(00)81336-7 . 18468998 . free .
• Serafini T, Colamarino SA, Leonardo ED, etal . Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. . Cell . 87 . 6 . 1001–14 . 1997 . 8978605 . 10.1016/S0092-8674(00)81795-X . 1008380 . free .
• Togari A, Mogi M, Arai M, etal . Expression of mRNA for axon guidance molecules, such as semaphorin-III, netrins and neurotrophins, in human osteoblasts and osteoclasts. . Brain Res. . 878 . 1–2 . 204–9 . 2001 . 10996153 . 10.1016/S0006-8993(00)02700-1 . 28322080 .
• Corset V, Nguyen-Ba-Charvet KT, Forcet C, etal . Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor . Nature . 407 . 6805 . 747–50 . 2000 . 11048721 . 10.1038/35037600 . 2000Natur.407..747C . 4423128 .
• Manitt C, Colicos MA, Thompson KM, etal . Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord . J. Neurosci. . 21 . 11 . 3911–22 . 2001 . 11356879 . 10.1523/JNEUROSCI.21-11-03911.2001. 6762706 .
• Srinivasan K, Strickland P, Valdes A, etal . Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis . Dev. Cell . 4 . 3 . 371–82 . 2003 . 12636918 . 10.1016/S1534-5807(03)00054-6 . free .
• Yebra M, Montgomery AM, Diaferia GR, etal . Recognition of the neural chemoattractant Netrin-1 by integrins alpha6beta4 and alpha3beta1 regulates epithelial cell adhesion and migration . Dev. Cell . 5 . 5 . 695–707 . 2003 . 14602071 . 10.1016/S1534-5807(03)00330-7 . free .
• Mazelin L, Bernet A, Bonod-Bidaud C, etal . Netrin-1 controls colorectal tumorigenesis by regulating apoptosis . Nature . 431 . 7004 . 80–4 . 2004 . 15343335 . 10.1038/nature02788 . 2004Natur.431...80M . 4417992 .
• Kato HD, Kondoh H, Inoue T, etal . Expression of DCC and netrin-1 in normal human endometrium and its implication in endometrial carcinogenesis . Gynecol. Oncol. . 95 . 2 . 281–9 . 2004 . 15491747 . 10.1016/j.ygyno.2004.07.050 .
• Kruger RP, Lee J, Li W, Guan KL . Mapping netrin receptor binding reveals domains of Unc5 regulating its tyrosine phosphorylation . J. Neurosci. . 24 . 48 . 10826–34 . 2005 . 15574733 . 10.1523/JNEUROSCI.3715-04.2004 . 6730211 . free .
• Hérincs Z, Corset V, Cahuzac N, etal . DCC association with lipid rafts is required for netrin-1-mediated axon guidance . J. Cell Sci. . 118 . Pt 8 . 1687–92 . 2005 . 15811950 . 10.1242/jcs.02296 . free .
• Kim TH, Lee HK, Seo IA, etal . Netrin induces down-regulation of its receptor, Deleted in Colorectal Cancer, through the ubiquitin-proteasome pathway in the embryonic cortical neuron . J. Neurochem. . 95 . 1 . 1–8 . 2005 . 16181408 . 10.1111/j.1471-4159.2005.03314.x . 2683579 .
• Ly NP, Komatsuzaki K, Fraser IP, etal . Netrin-1 inhibits leukocyte migration in vitro and in vivo . Proc. Natl. Acad. Sci. U.S.A. . 102 . 41 . 14729–34 . 2006 . 16203981 . 10.1073/pnas.0506233102 . 1253572 . 2005PNAS..10214729L . free .

Varadarajan, Supraja G., et al. "Netrin1 produced by neural progenitors, not floor plate cells, is required for axon guidance in the spinal cord." Neuron 94.4 (2017): 790-799.https://doi.org/10.1016/j.neuron.2017.03.007

Notes and References

1. Meyerhardt JA, Caca K, Eckstrand BC, Hu G, Lengauer C, Banavali S, Look AT, Fearon ER . Netrin-1: interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas . Cell Growth Differ. . 10 . 1 . 35–42 . January 1999 . 9950216.
2. Web site: Entrez Gene: NTN1 netrin 1.
3. Geisbrecht . Brian V . Dowd Kimberly A . Barfield Ronald W . Longo Patti A . Leahy Daniel J . Aug 2003 . Netrin binds discrete subdomains of DCC and UNC5 and mediates interactions between DCC and heparin . J. Biol. Chem. . 278 . 35 . 32561–8 . United States. 0021-9258. 12810718 . 10.1074/jbc.M302943200 . free .
4. Kryza D, Wischhusen J, Richaud M, Hervieu M, Sidi Boumedine J, Delcros JG, Besse S, Baudier T, Laval PA, Breusa S, Boutault E, Clermidy H, Rama N, Ducarouge B, Devouassoux-Shisheboran M, Chezal JM, Giraudet AL, Walter T, Mehlen P, Sarrut D, Gibert B.From netrin-1-targeted SPECT/CT to internal radiotherapy for management of advanced solid tumors. EMBO Mol Med. 2023 Apr 11;15(4):e16732. doi: 10.15252/emmm.202216732. Epub 2023 Mar 6. PMID 36876343
5. Pourchet . Oriane . Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements . Cell Reports . Jan 19, 2021 . 34 . 3 . 108654 . 10.1016/j.celrep.2020.108654 . 33472083. 231663364 . 10261/308989 . free .
6. Blockus . Heike . Chedotal . Alain . Slit-Robo signaling . Development . Sep 1, 2016 . 143 . 17 . 3037–3044 . 10.1242/dev.132829 . 27578174. 10315151 . free .