FETAL DEVELOPMENT OF THE ENTERIC NERVOUS-SYSTEM OF TRANSGENIC MICE THAT OVEREXPRESS THE HOXA-4 GENE

Megacolon occurs in neonatal and adult transgenic mice that overexpres s the Hoxa-4 gene. Abnormalities, which are restricted to the terminal colon of these mice, include a hypoganglionosis, abnormal enteric gan glia with a structure appropriate for extra-enteric peripheral nerve a nd not the enteric nervous system (ENS), and gaps in the longitudinal muscle occupied by ganglia. To investigate the developmental origin of these abnormalities, we analyzed the development of the pelvis and te rminal colon in Hoxa-4 transgenic mice. Morphological abnormalities we re detected as early as E13. These included an enlargement of the muco sa and the bowel wall, a thickening of the enteric mesenchyme, and the ectopic location of pelvic ganglion cells, which initially clustered on the dorsolateral wall of the hindgut. As the bowel enlarged, these ectopic cells become ventrolateral and, between days E17 and E18.5, ap peared to become incorporated into the gut, leaving neuron-filled gaps in the longitudinal muscle layer. The ectopic ganglia retained extra- enteric characteristics, including the presence of capillaries, basal laminae, collagen fibers, and catecholaminergic neurons, even after th eir incorporation into the bowel. It is proposed that the abnormal and ectopic expression of the Hoxa-4 transgene in the colon causes signal ling molecule(s) of the enteric mesenchyme to be overproduced and that the overabundance of these signals leads to mucosal enlargement and m isdirection of migrating pelvic neuronal progenitors. (C) 1998 Wiley-L iss, Inc.