Slit/Robo‐mediated chemorepulsion of vagal sensory axons in the fetal gut

Abstract

Background The vagus nerve descends from the brain to the gut during fetal life to reach specific targets in the bowel wall. Vagal sensory axons have been shown to respond to the axon guidance molecule netrin and to its receptor, deleted in colorectal cancer (DCC). As there are regions of the gut wall into which vagal axons do and do not extend, it is likely that a combination of attractive and repellent cues are involved in how vagal axons reach specific targets. We tested the hypothesis that Slit/Robo chemorepulsion can contribute to the restriction of vagal sensory axons to specific targets in the gut wall. Results Transcripts encoding Robo1 and Robo2 were expressed in the nodose ganglia throughout development and mRNA encoding the Robo ligands Slit1, Slit2, and Slit3 were all found in the fetal and adult bowel. Slit2 protein was located in the outer gut mesenchyme in regions that partially overlap with the secretion of netrin-1. Neurites extending from explanted nodose ganglia were repelled by Slit2. Conclusions These observations suggest that vagal sensory axons are responsive to Slit proteins and are thus repelled by Slits secreted in the gut wall and prevented from reaching inappropriate targets.

Slit2 expression and its correlation with subcellular localization of β-catenin in gastric cancer

“…We also noted that the positive staining of Slit2 was only observed in cells that located at the neck and bottom part of the glands, which were generally considered as normal gastric stem cells. As indicated in previous findings that Slit2 is involved in gut development (9), Slit2 may also play roles in gastric stem cells, thus explaining why Slit2 staining was only shown in a specific part of normal gastric glands. Dysplasia and intestinal metaplasia (IM) are two pre-cancerous lesions.…”

“…Slit2 is responsible for guiding neural cell migration by preventing inappropriate midline axonal crossing events (8). Recently, Slit2 was found to contribute to gut development (9). Slit2 protein was located in the outer gut mesenchyme in regions that partially overlap with the secretion of netrin-1.…”

“…Slit2 protein was located in the outer gut mesenchyme in regions that partially overlap with the secretion of netrin-1. Functionally, vagal sensory axons are responsive to Slit proteins and are thus repelled by Slits secreted in the gut wall and are prevented from reaching inappropriate targets (9).…”

Knockdown of Slit2 promotes growth and motility in gastric cancer cells via activation of AKT/β-catenin

“…Slit2 inhibits in vitro migration of various types of mammalian cells outside the CNS, such as leukocytes (7), dendritic cells (8) and vascular smooth muscle cells (9). Recently, Slit2 was found to contribute to gut development (10). Slit2 protein is located in the outer gut mesenchyme in regions that partially overlap with the secretion of netrin-1.…”

Development of the Autonomic Nervous System: Clinical Implications

“…59 The molecular mechanism used by vagal axons to navigate toward and innervate their wide array of target tissues is not fully understood, but there is evidence for the adhesion molecules Slit/Robo, netrin/DCC, and laminins in influencing the paths forged by developing vagal axons. 60,61 Recent single-cell RNA sequencing of nodose ganglion neurons has generated an "atlas" of differential gene expression patterns in clusters of nodose ganglion cells that should help us understand how different subclasses of nodose neurons establish and maintain their distinct identities. [62][63][64]…”