The centrally directed neurite of the dorsal root neuroblast has been described from the period of its initial entrance into the neural tube until a well-defined dorsal root is formed .

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The terminal portion of the ls/ls mouse is congenitally aganglionic because the precursors of enteric neurons fail to enter this region. This animal was studied in order to gain insight into the origin of enteric glia and into the process by which the precursors of these cells colonize the gut. In control (CD-1) mice, immunoreactivity of the glial marker, glial fibrillary acidic protein, appeared for the first time in the fetal bowel at day E16 and, in adults, was much more intense within intraenteric neural elements than in nerves outside the bowel. Glial fibrillary acidic protein developed in tissue cultures of fetal intestine explanted before the protein appeared in situ, and before the bowel became innervated by extrinsic nerves; thus, the precursors of cells able to elaborate glial fibrillary acidic protein must have been present, but unrecognizable, in the original explants. This explant assay demonstrated that these glial precursors were present in all regions of the bowel of control mice, but not in the presumptive aganglionic bowel of ls/ls mice. The nerves (of extrinsic origin) in the aganglionic tissue of ls/ls mice showed a high level of immunoreactive glial fibrillary acidic protein; nevertheless, their ultrastructure was typical of peripheral nerve, not enteric plexus, and they contained Schwann cells, not enteric glia. These observations support the view that enteric glia are derived from the single wave of neural crest colonists that populates the enteric nervous system before the gut receives its extrinsic innervation. These glial precursors, like neuronal precursors, tend to be excluded from the presumptive aganglionic ls/ls bowel. In contrast, Schwann cells grow into the abnormal ls/ls gut with the extrinsic innervation. The enteric microenvironment appears to promote the expression of glial fibrillary acidic protein in both enteric glia and Schwann cells; however, even within the bowel, Schwann cells retain their characteristic morphology. It is thus probable that the normal enteric nervous system contains supporting cells of separate lineages, enteric glia and Schwann cells.

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)

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