Aberrant Information Transfer Interferes with Functional Axon Regeneration

Abstract

12Functional axon regeneration requires regenerating neurons to restore appropriate synaptic 13 connectivity and circuit function. To model this process, we developed a single-neuron assay in C.

Activation of the CaMKII-Sarm1-ASK1 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria

“…To test whether the calsyntenin-CaMKII-MAPK pathway can prevent the late steps of degeneration that occur after axon breakage, we used laser axotomy to experimentally induce an axon break in one PVQ axon and examined the degeneration of the distal axon segment 24 hours later. Consistent with previous findings (Ding and Hammarlund, 2018;Nichols et al, 2016;Rawson et al, 2014), injury-induced degeneration of distal PVQ axon segments is slow, as nearly all axons are still present 24 hours later (Figure 1-figure supplement 2A-2B). By contrast, in ric-7(n2657) mutants, degeneration after injury is greatly enhanced due to the lack of axonal mitochondria (Figure 1-figure supplement 2A-2B) (Ding and Hammarlund, 2018;Nichols et al, 2016;Rawson et al, 2014).…”

“…Consistent with previous findings (Ding and Hammarlund, 2018;Nichols et al, 2016;Rawson et al, 2014), injury-induced degeneration of distal PVQ axon segments is slow, as nearly all axons are still present 24 hours later (Figure 1-figure supplement 2A-2B). By contrast, in ric-7(n2657) mutants, degeneration after injury is greatly enhanced due to the lack of axonal mitochondria (Figure 1-figure supplement 2A-2B) (Ding and Hammarlund, 2018;Nichols et al, 2016;Rawson et al, 2014). However, loss of calsyntenin or activation of CaMKII did not significantly suppress degeneration in ric-7(n2657) after axon transection (Figure 1-figure supplement 2B).…”

γ-Neurexin and Frizzled Mediate Parallel Synapse Assembly Pathways Antagonized by Receptor Endocytosis

“…The DA9 motor neuron is required for activation of the dorsal tail muscles, which when contracted lead to a dorsal tail bend. Expression of the red-shifted ChannelRhodopsin Chrimson (Klapoetke et al, 2014; Schild and Glauser, 2015) specifically in DA9 allows for temporally-precise DA9 activation along with visual analysis of dorsal tail bending in freely moving worms (Ding and Hammarlund, 2018). Wild type worms exhibit a highly synchronized and stereotyped dorsal tail bend upon green-light activation of DA9 Chrimson (Figure 6A).…”

Neurexin and Frizzled intercept axonal-transport at microtubule minus-ends to control synapse formation

“…DA9 optogenetic stimulation was performed as previously described (Ding and Hammarlund, 2018). Worms expressing Chrimson in DA9 were cultured on NGM plates seeded with OP50 containing 100 μM all-trans-retinal (ATR).…”

“…We next used a behavioral assay to ask if the observed molecular rescue of synaptic markers by VAB-8 overexpression corresponded with improved overall synapse function. We optogenetically stimulated DA9 and measured the angle of the resulting dorsal bending of the worm's tail (Ding and Hammarlund, 2018). nrx-1 mutants showed a mild but consistent reduction in dorsal bending of the tail (Figure 2I, J).…”