rab-27 acts in an intestinal pathway to inhibit axon regeneration in C. elegans

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.

The TWK-26 potassium channel governs nutrient absorption in theC. elegansintestine

“…Many of the factors that regulate the DMP have been studied in detail; however, the flr-4 and flr-1 mutations shorten the DMP cycle and cause expulsion defects for unclear reasons (Branicky and Hekimi 2006; Iwasaki et al 1995). The constipated phenotype, which likely results from improper expulsion of gut contents (Liu and Thomas 1994), coincides with intestine bloating (Gruss and Corsi 2022; Lin-Moore et al 2021). Intestine bloating can be indicative of increased microbial colonization, activation of innate immunity pathways, and initiation of pathogen aversion behaviors (Singh and Aballay 2019).…”

Endogenous hydrogen peroxide positively regulates secretion of a gut-derived peptide in neuroendocrine potentiation of the oxidative stress response inC. elegans

“…S1B). NLP-40 is a neuropeptide-like protein whose release from the intestine is presumed to be controlled by aex-1 , aex-3 , aex-4 and aex-6 (Lin-Moore, Oyeyemi, and Hammarlund 2021; Mahoney et al 2008; Shi et al 2022; Wang et al 2013). Null mutants in nlp-40 or its receptor, aex-2 (Wang et al 2013), exhibited normal juglone-induced FLP-1 secretion (Fig.…”

Cargo selective vesicle tethering: the structural basis for binding of specific cargo proteins by the Golgi tether component TBC1D23

“…NPDC1 is a largely uncharacterised protein suggested to play a role in neuropeptide secretion and dense core vesicle traffic ( 28 , 29 ), and the peptide from its tail has an affinity for TBC1D23 similar to that of syntaxin-16 at ∼3 µM (fig. S5).…”