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Axon pathfinding and neuronal migration are orchestrated by attractive and repulsive guidance cues. In the mouse spinal cord, repulsion from Slit proteins through Robo family receptors and attraction to Netrin-1, mediated by the receptor DCC, control many aspects of neural circuit formation. This includes motor neuron wiring, where Robos help prevent both motor neuron cell bodies and axons from aberrantly crossing the spinal cord midline. These functions had been ascribed to Robo signaling being required to counter DCC-mediated attraction to Netrin-1 at the midline, either by mediating repulsion from midline-derived Slits or by silencing DCC signaling. However, the role of DCC in promoting motor neuron and axon midline crossing had not been directly tested. Here, we usedin vivomouse genetics andin vitroaxon turning assays to further explore the interplay between Slit and Netrin signaling in motor neuron migration and axon guidance relative to the midline. We find that DCC is a major driver of midline crossing by motor axons, but not motor neuron cell bodies, whenRobo1andRobo2are knocked out. Further,in vitroresults indicate that Netrin-1 attracts motor axons and that Slits can modulate the chemotropic response to Netrin-1, converting it from attraction to repulsion. Our findings indicate that Robo signaling allows both motor neuron cell bodies and axons to avoid the midline, but that only motor axons require this pathway to antagonize DCC-dependent midline attraction, which likely involves a combination of mediating Slit repulsion and directly influencing Netrin-DCC signaling output.
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The scheduling of adolescence with Netrin-1 and UNC5C
Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons toward the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1-expressing cells – disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters;Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner – delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.
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- Award ID(s):
- 1754878
- PAR ID:
- 10541229
- Publisher / Repository:
- eLife Sciences Publications Ltd
- Date Published:
- Journal Name:
- eLife
- Volume:
- 12
- ISSN:
- 2050-084X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.7554/eLife.88261.4
