Abstract
Adult neurogenesis rarely occurs in the enteric nervous system (ENS). In this study, we demonstrated that, after intestinal myenteric plexus (MP) ablation with benzalkonium chloride (BAC), adult neurogenesis in the ENS was significantly induced in c-kit loss-of-function mutant mice (W/Wv). Almost all neurons and fibers in the MP disappeared after BAC treatment. However, 1 week after ablation, substantial penetration of nerve fibers from the non-damaged area was observed in the MP, longitudinal muscle and subserosal layers in both wildtype and W/Wv mice. Two weeks after BAC treatment, in addition to the penetrating fibers, a substantial number of ectopic neurons appeared in the subserosal and longitudinal muscle layers of W/Wv mice, whereas only a few ectopic neurons appeared in wildtype mice. Such ectopic neurons expressed either excitatory or inhibitory intrinsic motor neuron markers and formed ganglion-like structures, including glial cells, synaptic vesicles and basal lamina. Furthermore, oral administration of imatinib, an inhibitor of c-Kit and an anticancer agent for gastrointestinal stromal tumors, markedly induced appearance of ectopic neurons after BAC treatment, even in wildtype mice. These results suggest that adult neurogenesis in the ENS is negatively regulated by c-Kit signaling in vivo.
Highlights
Maintenance[11,12,13]
One week after BAC treatment, newly appearing NADPH+nerves were observed in the longitudinal muscle (LM), SS and myenteric plexus (MP)
Because NADPH+neurons are usually classified as intrinsic inhibitory motor neurons, we investigated the existence of intrinsic excitatory motor neurons, whose processes are elongated into the LM from the MP24, using calretinin as a marker
Summary
Maintenance[11,12,13]. Gain-of-function mutations of c-Kit exist in the gastrointestinal stromal tumor (GISTs), the most common mesenchymal tumors in the human gastrointestinal tract. The c-kit gene is allelic with the murine white-spotting locus (W) and a heterozygote for two distinct mutations occurs in the W/Wv strain. These are a deletion in the c-Kit transmembrane domain (W) and a point mutation in the c-Kit kinase domain (Wv)[17,18,19]. In a series of studies using W/Wv mice, we examined effects of BAC ablation on intestinal neurons. We noticed, in addition to intestinal neuronal ablation, the appearance of ectopic neurons in the longitudinal muscle (LM) and the subserosal (SS) layers in W/Wv mice treated with BAC. To investigate whether the appearance of ectopic neurons was incidental or, instead, associated with a certain condition, we here examined the conditions leading to appearance of these neurons and addressed potential mechanisms underlying their appearance
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