Abstract
The molecular mechanisms underlying the ability of axons to regenerate after injury remain poorly understood. Here we show that in Caenorhabditis elegans, axotomy induces ectopic expression of serotonin (5-HT) in axotomized non-serotonergic neurons via HIF-1, a hypoxia-inducible transcription factor, and that 5-HT subsequently promotes axon regeneration by autocrine signalling through the SER-7 5-HT receptor. Furthermore, we identify the rhgf-1 and rga-5 genes, encoding homologues of RhoGEF and RhoGAP, respectively, as regulators of axon regeneration. We demonstrate that one pathway initiated by SER-7 acts upstream of the C. elegans RhoA homolog RHO-1 in neuron regeneration, which functions via G12α and RHGF-1. In this pathway, RHO-1 inhibits diacylglycerol kinase, resulting in an increase in diacylglycerol. SER-7 also promotes axon regeneration by activating the cyclic AMP (cAMP) signalling pathway. Thus, HIF-1-mediated activation of 5-HT signalling promotes axon regeneration by activating both the RhoA and cAMP pathways.
Highlights
The molecular mechanisms underlying the ability of axons to regenerate after injury remain poorly understood
We show that the hypoxia-inducible transcription factor (HIF-1) induces expression of the tph-1 gene in axotomized neurons, which are not serotonergic. 5-HT subsequently promotes axon regeneration by signalling through the serotonin receptor SER-7
We found that the RGA-5 GTPase-activating protein (GAP) domain (1118–1341 amino acids) interacted with the GTP bound, but not GDP-bound version of RHO-1 (Fig. 4b), consistent with the property of GAP proteins to associate with the GTP-bound version of GTPases
Summary
The molecular mechanisms underlying the ability of axons to regenerate after injury remain poorly understood. To match serotonin levels to the normal range for each neuron, we used a system recently developed by Flavell et al.[11] A single floxed copy of the tph-1 gene, including the promoter, exons and introns, was inserted into a defined location on chromosome IV (Fig. 1e) This inserted gene was able to rescue the tph-1 defect in axon regeneration of D-type motor neurons (Fig. 1f and Supplementary Table 2). This was combined with cell-specific transgenes expressing Cre recombinase in amphid sensory neuron, dual cilia, designation F. Expression of tph-1 in ADF neurons by the srh-142 promoter was unable to rescue the tph-1 defect (Fig. 1d and Supplementary Table 2) These results suggest that axon regeneration in D-type motor neurons requires 5-HT production by D neurons. These results demonstrate that TPH-1 acts to promote regeneration of the damaged neuron in a cell-autonomous manner
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