Microenvironmental factors in the normal and abnormal development of the enteric nervous system

Abstract

In order to gain insight into the molecular nature of some of the interactions that shape the ontogeny of the ENS, we have been studying two murine models in which enteric neural development is abnormal. One is the lethal spotted (ls/ls) mutant mouse. The other is a line of transgenic mice ("1975-2") that overexpress a homeobox-containing gene, Hox-1.4. Megacolon, an expansion of the bowel proximal to an abnormally innervated terminal gut, develops in each of these mice; however, the animals differ with respect to the nature of their neural defect. In ls/ls mice the terminal bowel is congenitally aganglionic (although hyperinnervated with nerve processes), because it cannot be colonized by migrating crest-derived cells. In contrast, the terminal gut of the transgenic (1975-2) mice contains ganglia, but the ultrastructure of these ganglia is that of peripheral, not enteric, nerve. On the basis of observations made thus far, we postulate that the ls/ls defect arises as a result of an overabundance and maldistribution of molecular components of basal laminae (such as laminin), which we have observed in the presumptive aganglionic bowel. We propose that crest-derived cells acquire a nerve-related laminin receptor when they enter the gut, which, when activated, induces these cells to withdraw from the cell cycle, differentiate, and extend neurites (or glial processes). Excessive laminin causes this response to occur prematurely. Cells that differentiate into neurons or glia presumably no longer migrate; therefore, the bowel distal to the region in which they respond to the abnormal extracellular ls/ls matrix does not become colonized by crest-derived cells. The molecular defect in the 1975-2 animals is unknown, but it would appear that it interferes, not with the migration of crest-derived cells, but with their subsequent differentiation along lineages appropriate to the bowel. Since the Hox-1.4 gene is overexpressed throughout the length of the gut, and not just in the abnormal section, we propose that prolonged exposure of neural precursors to cells that overexpress the Hox-1.4 gene product, renders the neural precursors unresponsive to the effects of the enteric microenvironment on neural differentiation. The abnormal zone of the 1975-2 bowel, therefore, is the region last to be colonized by crest-derived cells.