FETAL ENDODERM PRIMARILY HOLDS THE TEMPORAL AND POSITIONAL INFORMATION REQUIRED FOR MAMMALIAN INTESTINAL DEVELOPMENT

In rodents, the intestinal tract progressively acquires a functional r egionalization during postnatal development. Using lactase-phlorizin h ydrolase as a marker, we have analyzed in a xenograft model the ontoge nic potencies of fetal rat intestinal segments taken prior to endoderm cytodifferentiation. Segments from the presumptive proximal jejunum a nd distal ileum grafted in nude mice developed correct spatial and tem poral patterns of lactase protein and mRNA expression, which reproduce d the normal pre- and post-weaning conditions. Segments from the fetal colon showed a faint lactase immunostaining 8-10 d after transplantat ion in chick embryos but not in mice; it is consistent with the transi ent expression of this enzyme in the colon of rat neonates. Heterotopi c cross-associations comprising endoderm and mesenchyme from the presu mptive proximal jejunum and distal ileum developed as xenografts in nu de mice, and they exhibited lactase mRNA and protein expression patter ns that were typical of the origin of the endodermal moiety. Endoderm from the distal ileum also expressed a normal lactase pattern when it was associated to fetal skin fibroblasts, while the fibroblasts differ entiated into muscle layers containing alpha-smooth-muscle actin. Note worthy, associations comprising colon endoderm and small intestinal me senchyme showed a typical small intestinal morphology and expressed th e digestive enzyme sucrase-isomaltase normally absent in the colon. Ho wever, in heterologous associations comprising lung or stomach endoder m and small intestinal mesenchyme, the epithelial compartment expresse d markers in accordance to their tissue of origin but neither intestin al lactase nor sucrase-isomaltase. A thick intestinal muscle coat in w hich cells expressed alpha-smooth-muscle actin surrounded the grafts. The results demonstrate that: (a) the temporal and positional informat ion needed for intestinal ontogeny up to the post-weaning stage result s from an intrinsic program that is fixed in mammalian fetuses prior t o endoderm cytodifferentiation; (b) this temporal and positional infor mation is primarily carried by the endodermal moiety which is also abl e to change the fate of heterologous mesodermal cells to form intestin al mesenchyme; and (c) the small intestinal mesenchyme in turn may del iver instructive information as shown in association with colonic endo derm; yet this effect is not obvious with nonintestinal endoderms.