Origin and morphology of nerve fibers the aganglionic colon of the lethal spotted (ls/ls) mutant mouse

Abstract

The lethal spotted mutant mouse (ls/ls) develops congenital megacolon because of the absence of ganglia in the terminal colon. This aganglionosis results from a failure of neural crest cells to colonize this area during fetal life. We have postulated that the microenvironment of the aganglionic segment of bowel is abnormal. Our hypothesis suggests that this abnormal enteric microenvironment fosters the sprouting of neuritic processes. We further propose that neural and glial precursors cease to migrate once they have extended their definitive processes. As a result, the area distal to the site where neurite extension is favored does not become colonized by neural or glial precursors. A prediction of this hypothesis is that the aganglionic tissue should be innervated by axons from neurons located both in the more proximal ganglionated bowel and in ganglia located outside the gut. Neurons and their processes in control and ls/ls terminal gut were located by the histochemical demonstration of acetylcholinesterase (AChE) activity and their structure was classified as intrinsic (enteric) or extrinsic in type by electron microscopy. In ls/ls mice the submucosal plexus was much more severely affected than the myenteric plexus. No submucosal ganglia were found within 30 mm of the anus. In contrast, myenteric ganglia extended to within 4 mm of the anus on the mesenteric side of the gut and to within 15 mm on the antimesenteric side. Rostral to the areas that were absolutely aganglionic, both plexuses were hypoganglionic, especially the submucosal plexus, which was hypoganglionic throughout the entire colon. Both the aganglionic and caudal hypoganglionic zones of the ls/ls bowel were penetrated by large nerve trunks that had the ultrastructural characteristics of extra-enteric peripheral nerve. Unusual ganglia, outside the enteric musculature in the adventitia of the colon, were connected to these trunks. The location of the cell bodies of origin of the nerve fibers in the terminal colon of control mice and in the aganglionic segment of the bowel in ls/ls mice was determined by following the retrograde transport of tracers injected as close as possible to the anus. An extrinsic innervation originating from the inferior mesenteric ganglion and dorsal root ganglia (L6-S1) was found in both types of animal. In control but not ls/ls mice retrograde labeling was also observed in the sacral parasympathetic nucleus of the spinal cord. In addition, neuritic processes were traced to neurons in myenteric ganglia. In control mice, these labeled neurons were present in ganglia within the injection site as well as in bowel rostral and caudal to it.(ABSTRACT TRUNCATED AT 400 WORDS)

Colonization of the bowel by neural crest‐derived cells re‐migrating from foregut backtransplanted to vagal or sacral regions of host embryos

“…Re-migrating cells may also be found in either the myenteric plexus, which forms first, or the submucosal plexus, which develops at a later age, following the formation of the circular muscle. The submucosal plexus has been postulated to form as a result of a secondary migration of cells from the myenteric Gershon et al, 1980;Payette et al, 1987;Pomeranz and Gershon, 1990). If this is true, some of the re-migrating enteric crest-derived cells evidently retain their ability to relocate themselves even after they have traveled to the bowel for a second time.…”

Structural abnormalities associated with congenital megacolon in transgenic mice that overexpress the Hoxa‐4 gene

“…Another similarity is that both Zslls mice Payette et al, 1987) and transgenic mice have abnormal ganglia in the adventitia in the affected terminal segment of Figure 108. Neurons (N), axons r), and supporting cell processes are separated by only a thin basement membrane (arrowheads) from the adventitia (ad), which contains collagen and elastic fibrils.…”

“…We have shown by retrograde labeling of the adult lslls mouse that some of the axons in the aganglionic lslls colon arise from neuronal cell bodies in the rostral near-normal myenteric plexus, whereas other axons are from the sacral dorsal root ganglia and sympathetic ganglia (Payette et al, 1987). We have not done retrograde labeling on transgenic mice, but it is likely that there is some abnormal ingrowth of extrinsic axons into the terminal colon in these animals as well.…”

“…After several rinses in buffer, laminar (split thickness) preparations were made by teasing the colon into two specimens along the junction of the circular muscle layer and the submucosa. The internal specimen consisting of the submucosa and mucosa was not included in this study because the submucosal ganglia were relatively sparse and randomly distributed even in the control caudal colon (Payette et al, 1987) and thus, provided little material for study. The external specimen contained the two muscle layers of the muscularis externa, the intermuscular region where the myenteric plexus is found in control mice, and the adventitialserosa.…”

The development of colon innervation in trisomy 16 mice and Hirschsprungs disease

“…These excessive accumulation of basal lamina material and muscularis mucosa interfered with normal migration of precursor cells [47][48][49][50][51] . Payette and associates [52] thought that the excessive accumulation of components of basal lamina material in the aganglionic region of the lethal spotted mutant mouse stopped precursor cells from migrating into the terminal bowel of lethal spotted mutant mice.…”