Abstract
Injured axons must regenerate to restore nervous system function, and regeneration is regulated in part by external factors from non-neuronal tissues. Many of these extrinsic factors act in the immediate cellular environment of the axon to promote or restrict regeneration, but the existence of long-distance signals regulating axon regeneration has not been clear. Here we show that the Rab GTPase rab-27 inhibits regeneration of GABAergic motor neurons in C. elegans through activity in the intestine. Re-expression of RAB-27, but not the closely related RAB-3, in the intestine of rab-27 mutant animals is sufficient to rescue normal regeneration. Several additional components of an intestinal neuropeptide secretion pathway also inhibit axon regeneration, including NPDC1/cab-1, SNAP25/aex-4, KPC3/aex-5, and the neuropeptide NLP-40, and re-expression of these genes in the intestine of mutant animals is sufficient to restore normal regeneration success. Additionally, NPDC1/cab-1 and SNAP25/aex-4 genetically interact with rab-27 in the context of axon regeneration inhibition. Together these data indicate that RAB-27-dependent neuropeptide secretion from the intestine inhibits axon regeneration, and point to distal tissues as potent extrinsic regulators of regeneration.
Highlights
Unlike many other tissues, where cells respond to injury through proliferation and replacement, cells in the nervous system are not usually replaced following axon damage
C. elegans provides a robust system to investigate in vivo axon regeneration at single-neuron resolution [9]
This work demonstrated that Rab27B/rab-27 inhibits regeneration in both mouse and C. elegans models, and indicated that one site of function for RAB-27 in C. elegans is in the injured neurons
Summary
Since most neurons are not replaced over an organism’s lifetime, neurons must regenerate damaged axons in order to restore function after injury. Despite the importance of regeneration to organism function, behavior and survival, regeneration is often actively inhibited in mature animals. Our results show that distant tissues can block regeneration. We show for the first time that the intestine secretes factors that inhibit axon regeneration, and that blocking this pathway improves regeneration. Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files.
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