STRUCTURAL ABNORMALITIES ASSOCIATED WITH CONGENITAL MEGACOLON IN TRANSGENIC MICE THAT OVEREXPRESS THE HOXA-4 GENE

Congenital megacolon develops in transgenic mice that overexpress the homeobox-containing gene, Hoxa4. The current study was done to identif y abnormalities of the terminal colon that might account for the pheno type. The terminal bowel of transgenic mice was compared with that of control and lethal spotted (ls/ls) mice, a strain in which megacolon a lso develops. The terminal colon of the transgenic mice contained fewe r ganglia than that of controls, but was hypoganglionic, rather than a ganglionic like that of ls/ls mice. The neurons present in the adult t ransgenic colon were significantly increased in size and a subset of v ery large neurons (>40 mum in maximum diameter) were observed. Electro n microscopic studies of young adult transgenic mice revealed that the ganglia and nerves of the myenteric plexus had the ultrastructure of extraenteric peripheral nerve rather than that of the enteric nervous system (ENS). The myenteric ganglia in the transgenic animals containe d Schwann cells associated with a basal lamina that enveloped axons co mpletely and individually, instead of glia. Although collagen is exclu ded from the ganglia and thin nerve fibers of the normal ENS, a collag en-containing endoneurium surrounded each of the axon-Schwann cell uni ts of the abnormal nerve fibers of the transgenic colon. Some of the n eurons of the transgenic mice were located in these nerve bundles rath er than in ganglia. There were also smooth muscle abnormalities in the terminal bowel of the transgenic mice. Wide gaps were present in the longitudinal muscle of the transgenic mice; these gaps contained gangl ia that were in contact with the adventitia. These longitudinal smooth muscle cells were more irregular than those of controls and they cont ained fewer puncta adherens; moreover, a larger proportion of the volu me of the cytoplasm of transgenic smooth muscle cells was occupied by organelles. Finally, an extensive thickening and reduplication of the basal lamina surrounding the smooth muscle cells of the muscularis muc osa was observed in the transgenic colon and resembled that found in l s/ls mice. These data suggest that both smooth muscle and the innervat ion of the terminal bowel of neonatal Hoxa-4 transgenic mice are struc turally abnormal. Although some of the abnormalities seen in Hoxa-4 tr ansgenic mice are similar to those which arise in ls/ls mice, the two conditions are not identical. In both animals, the data are consistent with the hypothesis that the defects arise as a result of a defective interaction between the precursors of enteric neurons and smooth musc le. (C) 1993 Wiley-Liss, Inc.