Diversity and Specificity of Actions of Slit2 Proteolytic Fragments in Axon Guidance

Overview

Journal J Neurosci

Specialty Neurology

Date 2001 Jun 19

PMID 11404413

Citations 77

Authors

K Brose

L Ma

K H Wang

V Marillat

C Sotelo

M Tessier-Lavigne

A Chedotal

Affiliations

Soon will be listed here.

Abstract

The Slits are secreted proteins that bind to Robo receptors and play a role in axon guidance and neuronal migration. In vertebrates, Slit2 is a major chemorepellent for developing axons and is involved in the control of midline crossing. In vivo, Slit2 is cleaved into 140 kDa N-terminal (Slit2-N) and 55-60 kDa C-terminal (Slit2-C) fragments, although the uncleaved/full-length form can also be isolated from brain extract. We explored the functional activities of Slit2 fragments by engineering mutant and truncated versions of Slit2 representing the N-, C-, and full/uncleavable (Slit2-U) fragments. Only Slit2-N and Slit2-U bind the Robo proteins. We found that in collagen gel, olfactory bulb (OB) but not dorsal root ganglia (DRG) axons are repelled by Slit2-N and Slit2-U. Moreover, only Slit2-N membranes or purified protein-induced OB growth cones collapse. Finally, we found that only recombinant Slit2-N could induce branching of DRG axons and that this effect was antagonized by Slit2-U. Therefore, different axons have distinct responses to Slit2 fragments, and these proteins have different growth-promoting capacities.

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References

Zhu Y, Li H, Zhou L, Wu J, Rao Y . Cellular and molecular guidance of GABAergic neuronal migration from an extracortical origin to the neocortex. Neuron. 1999; 23(3):473-85. DOI: 10.1016/s0896-6273(00)80801-6. View

Adams R, Lohrum M, Klostermann A, Betz H, Puschel A . The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. EMBO J. 1997; 16(20):6077-86. PMC: 1326291. DOI: 10.1093/emboj/16.20.6077. View

Holmes G, Negus K, Burridge L, Raman S, Algar E, Yamada T . Distinct but overlapping expression patterns of two vertebrate slit homologs implies functional roles in CNS development and organogenesis. Mech Dev. 1999; 79(1-2):57-72. DOI: 10.1016/s0925-4773(98)00174-9. View

Rudenko G, Nguyen T, Chelliah Y, Sudhof T, Deisenhofer J . The structure of the ligand-binding domain of neurexin Ibeta: regulation of LNS domain function by alternative splicing. Cell. 1999; 99(1):93-101. DOI: 10.1016/s0092-8674(00)80065-3. View

Lee J, Ekker S, von Kessler D, Porter J, Sun B, Beachy P . Autoproteolysis in hedgehog protein biogenesis. Science. 1994; 266(5190):1528-37. DOI: 10.1126/science.7985023. View

Liang Y, Annan R, Carr S, Popp S, Mevissen M, Margolis R . Mammalian homologues of the Drosophila slit protein are ligands of the heparan sulfate proteoglycan glypican-1 in brain. J Biol Chem. 1999; 274(25):17885-92. DOI: 10.1074/jbc.274.25.17885. View

Brose K, Bland K, Wang K, Arnott D, Henzel W, Goodman C . Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell. 1999; 96(6):795-806. DOI: 10.1016/s0092-8674(00)80590-5. View

Hattori M, Osterfield M, Flanagan J . Regulated cleavage of a contact-mediated axon repellent. Science. 2000; 289(5483):1360-5. DOI: 10.1126/science.289.5483.1360. View

Stoeckli E, Landmesser L . Axon guidance at choice points. Curr Opin Neurobiol. 1998; 8(1):73-9. DOI: 10.1016/s0959-4388(98)80010-x. View

10.

Li H, Chen J, Wu W, Fagaly T, Zhou L, Yuan W . Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons. Cell. 1999; 96(6):807-18. DOI: 10.1016/s0092-8674(00)80591-7. View

11.

Galko M, Tessier-Lavigne M . Biochemical characterization of netrin-synergizing activity. J Biol Chem. 2000; 275(11):7832-8. DOI: 10.1074/jbc.275.11.7832. View

12.

Porter J, Ekker S, Park W, von Kessler D, Young K, Chen C . Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell. 1996; 86(1):21-34. DOI: 10.1016/s0092-8674(00)80074-4. View

13.

Niclou S, Jia L, Raper J . Slit2 is a repellent for retinal ganglion cell axons. J Neurosci. 2000; 20(13):4962-74. PMC: 6772294. View

14.

Hu H . Chemorepulsion of neuronal migration by Slit2 in the developing mammalian forebrain. Neuron. 1999; 23(4):703-11. DOI: 10.1016/s0896-6273(01)80029-5. View

15.

Rothberg J, Artavanis-Tsakonas S . Modularity of the slit protein. Characterization of a conserved carboxy-terminal sequence in secreted proteins and a motif implicated in extracellular protein interactions. J Mol Biol. 1992; 227(2):367-70. DOI: 10.1016/0022-2836(92)90891-m. View

16.

Wang K, Brose K, Arnott D, Kidd T, Goodman C, Henzel W . Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching. Cell. 1999; 96(6):771-84. DOI: 10.1016/s0092-8674(00)80588-7. View

17.

de Castro F, Hu L, Drabkin H, Sotelo C, Chedotal A . Chemoattraction and chemorepulsion of olfactory bulb axons by different secreted semaphorins. J Neurosci. 1999; 19(11):4428-36. PMC: 6782631. View

18.

Seeds N, Siconolfi L, Haffke S . Neuronal extracellular proteases facilitate cell migration, axonal growth, and pathfinding. Cell Tissue Res. 1997; 290(2):367-70. DOI: 10.1007/s004410050942. View

19.

Dodd J, Morton S, Karagogeos D, Yamamoto M, Jessell T . Spatial regulation of axonal glycoprotein expression on subsets of embryonic spinal neurons. Neuron. 1988; 1(2):105-16. DOI: 10.1016/0896-6273(88)90194-8. View

20.

Hohenester E, Tisi D, Talts J, Timpl R . The crystal structure of a laminin G-like module reveals the molecular basis of alpha-dystroglycan binding to laminins, perlecan, and agrin. Mol Cell. 2000; 4(5):783-92. DOI: 10.1016/s1097-2765(00)80388-3. View