| Structural highlights
Function
UNC6_CAEEL Component of an extracellular matrix cue that guides dorsoventral migrations on the epidermis (PubMed:8861903). Required for the guidance of pioneer axons and migrating cells along the body wall (PubMed:28846083, PubMed:8332188). In particular, it is required for the guidance of axons from neurons, including SubL neurons and AIY interneurons, into the nerve ring (PubMed:28846083, PubMed:9473333). During gonad morphogenesis, involved in distal tip cell (DTC) migration from the dorsal side of the hermaphrodite body to the midbody to allow for formation of gonad arms (PubMed:17716643, PubMed:22732572). Its association with either unc-40 or unc-5 receptors will lead to axon attraction or repulsion, respectively (PubMed:8332188, PubMed:8861903, PubMed:9473333). Involved in dendritic morphogenesis; may act by association with unc-40 at the tips of growing dendrites for interaction with unc-5 on the apposing branch to induce mutual repulsion (PubMed:22426253). Involved in the positioning of ray 1, the most anterior ray sensilium, in the male tail (PubMed:24004945). Required for the formation of synapses between the AVA interneurons and the PHB sensory neurons (PubMed:29742100).[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
Netrins dictate attractive and repulsive responses during axon growth and cell migration, where the presence of the receptor Uncoordinated-5 (UNC-5) on target cells results in repulsion. Here, we showed that UNC-5 is a heparin-binding protein, determined its structure bound to a heparin fragment, and could modulate UNC-5-heparin affinity using a directed evolution platform or structure-based rational design. We demonstrated that UNC-5 and UNC-6/netrin form a large, stable, and rigid complex in the presence of heparin, and heparin and UNC-5 exclude the attractive UNC-40/DCC receptor from binding to UNC-6/netrin to a large extent. Caenorhabditis elegans with a heparin-binding-deficient UNC-5 fail to establish proper gonad morphology due to abrogated cell migration, which relies on repulsive UNC-5 signaling in response to UNC-6. Combining UNC-5 mutations targeting heparin and UNC-6/netrin contacts results in complete cell migration and axon guidance defects. Our findings establish repulsive netrin responses to be mediated through a glycosaminoglycan-regulated macromolecular complex.
Structural insights into the formation of repulsive netrin guidance complexes.,Priest JM, Nichols EL, Smock RG, Hopkins JB, Mendoza JL, Meijers R, Shen K, Ozkan E Sci Adv. 2024 Feb 16;10(7):eadj8083. doi: 10.1126/sciadv.adj8083. Epub 2024 Feb , 16. PMID:38363837[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zheng H, Coudiere L, Camia C, Colavita A, Culotti JG, Merz DC. C. elegans seu-1 encodes novel nuclear proteins that regulate responses to UNC-6/netrin guidance cues. Dev Biol. 2007 Oct 1;310(1):44-53. doi: 10.1016/j.ydbio.2007.07.014. Epub 2007 , Jul 24. PMID:17716643 doi:http://dx.doi.org/10.1016/j.ydbio.2007.07.014
- ↑ Smith CJ, Watson JD, VanHoven MK, Colon-Ramos DA, Miller DM 3rd. Netrin (UNC-6) mediates dendritic self-avoidance. Nat Neurosci. 2012 Mar 18;15(5):731-7. doi: 10.1038/nn.3065. PMID:22426253 doi:http://dx.doi.org/10.1038/nn.3065
- ↑ Martynovsky M, Wong MC, Byrd DT, Kimble J, Schwarzbauer JE. mig-38, a novel gene that regulates distal tip cell turning during gonadogenesis in C. elegans hermaphrodites. Dev Biol. 2012 Aug 15;368(2):404-14. doi: 10.1016/j.ydbio.2012.06.011. Epub 2012 , Jun 23. PMID:22732572 doi:http://dx.doi.org/10.1016/j.ydbio.2012.06.011
- ↑ Dalpe G, Tarsitano M, Persico MG, Zheng H, Culotti J. C. elegans PVF-1 inhibits permissive UNC-40 signalling through CED-10 GTPase to position the male ray 1 sensillum. Development. 2013 Oct;140(19):4020-30. doi: 10.1242/dev.095190. Epub 2013 Sep 4. PMID:24004945 doi:http://dx.doi.org/10.1242/dev.095190
- ↑ Rapti G, Li C, Shan A, Lu Y, Shaham S. Glia initiate brain assembly through noncanonical Chimaerin-Furin axon guidance in C. elegans. Nat Neurosci. 2017 Oct;20(10):1350-1360. doi: 10.1038/nn.4630. Epub 2017 Aug 28. PMID:28846083 doi:http://dx.doi.org/10.1038/nn.4630
- ↑ Varshney A, Benedetti K, Watters K, Shankar R, Tatarakis D, Coto Villa D, Magallanes K, Agenor V, Wung W, Farah F, Ali N, Le N, Pyle J, Farooqi A, Kieu Z, Bremer M, VanHoven M. The receptor protein tyrosine phosphatase CLR-1 is required for synaptic partner recognition. PLoS Genet. 2018 May 9;14(5):e1007312. doi: 10.1371/journal.pgen.1007312. , eCollection 2018 May. PMID:29742100 doi:http://dx.doi.org/10.1371/journal.pgen.1007312
- ↑ Hamelin M, Zhou Y, Su MW, Scott IM, Culotti JG. Expression of the UNC-5 guidance receptor in the touch neurons of C. elegans steers their axons dorsally. Nature. 1993 Jul 22;364(6435):327-30. PMID:8332188 doi:http://dx.doi.org/10.1038/364327a0
- ↑ Chan SS, Zheng H, Su MW, Wilk R, Killeen MT, Hedgecock EM, Culotti JG. UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. Cell. 1996 Oct 18;87(2):187-95. doi: 10.1016/s0092-8674(00)81337-9. PMID:8861903 doi:http://dx.doi.org/10.1016/s0092-8674(00)81337-9
- ↑ Colavita A, Culotti JG. Suppressors of ectopic UNC-5 growth cone steering identify eight genes involved in axon guidance in Caenorhabditis elegans. Dev Biol. 1998 Feb 1;194(1):72-85. doi: 10.1006/dbio.1997.8790. PMID:9473333 doi:http://dx.doi.org/10.1006/dbio.1997.8790
- ↑ Priest JM, Nichols EL, Smock RG, Hopkins JB, Mendoza JL, Meijers R, Shen K, Özkan E. Structural insights into the formation of repulsive netrin guidance complexes. Sci Adv. 2024 Feb 16;10(7):eadj8083. PMID:38363837 doi:10.1126/sciadv.adj8083
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