Regulation of commissural axon pathfinding by SLIT and ROBO

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Homo sapiens
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Commissural axons project to the floor plate, attracted by the interaction of their DCC receptors with Netrin-1 (NTN1) produced by floor plate cells (Dickson and Gilestro 2006) and radial glia (Dominici et al. 2017, Varadarajan et al. 2017). Once an axon enters the floor plate, it must be efficiently expelled on the contralateral side. A switch from attraction to repulsion allows commissural axons to enter and then leave the CNS midline. Based on studies in Xenopus neurons and by yeast two hybrid screens, it is observed that the attractive response of axons to netrins is silenced by activation of ROBO. SLIT bound ROBO binds to DCC, preventing it from transducing an attractive response to netrin. The sensitivity of axons to the repulsive action of SLIT does not only depend on repulsive SLIT receptors (ROBO1 and ROBO2), but is also influenced by expression of ROBO3, a SLIT receptor that suppresses the activity of ROBO1 and ROBO2. Upon crossing the midline, commissural axons downregulate expression of ROBO3 and increase expression of ROBO1/ROBO2 (reviewed by Dickson and Gilestro, 2006). Two transcript variants of ROBO3, ROBO3.1 and ROBO3.2 are considered to play different roles in midline crossing. ROBO3.1 is expressed in the pre-crossing and crossing commissural axons, while ROBO3.2, generated by alternative splicing, is expressed after midline crossing and thought to block midline re-crossing (Chen et al. 2008). In addition to SLITs, a secreted ligand NELL2 also acts as an axonal guidance cue that, by acting through ROBO3 receptors, helps to steer commissural axons to the midline. Both ROBO3.1 and ROBO3.2 can bind to a secreted ligand NELL2. Pre-crossing commissural axons, which express ROBO3.1, are repelled by NELL2. Post-crossing axons, which express ROBO3.2 are not repelled by NELL2 (Jaworski et al. 2015). .
Literature References
PubMed ID Title Journal Year
28434801 Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord

Varadarajan, SG, Phan, KD, Kania, A, Novitch, BG, Kong, JH, Panaitof, SC, Butler, SJ, Eltzschig, H, Cardin, J, Kao, TJ

Neuron 2017
17029581 Regulation of commissural axon pathfinding by slit and its Robo receptors

Gilestro, GF, Dickson, BJ

Annu Rev Cell Dev Biol 2006
28445456 Floor-plate-derived netrin-1 is dispensable for commissural axon guidance

Puiggros, SR, Rama, N, Rappeneau, Q, Moreno-Bravo, JA, Mehlen, P, Dominici, C, Vieugue, P, Ch├ędotal, A, Bernet, A

Nature 2017
26586761 Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2

Jaworski, A, Tong, RK, Gildea, HK, Tom, I, Gonzalez, LC, Koch, AW, Tessier-Lavigne, M

Science 2015
18466743 Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion

Gore, BB, Ma, L, Long, H, Tessier-Lavigne, M, Chen, Z

Neuron 2008
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