Repressive and restrictive mesodermal interactions with gut endoderm: possible relation to Meckel's Diverticulum

The midgut and hindgut endoderm of the mouse embryo give rise to the intest inal epithelium, yet it is not known how the intestinal program is chosen i n contrast to other endoderm-derived cell types. Previous tissue explant st udies with embryos at 8.5 to 11.5 days gestation (d) showed that when the g ut mesoderm is removed from the prospective intestinal endoderm, the endode rm activates the expression of liver-specific genes such as serum albumin, demonstrating the endoderm's pluripotence. This reversible repression of li ver genes does not affect the expression of the endodermal transcription fa ctors HNF3 and GATA4 nor these factors' ability to engage target sites in c hromatin, We have now found that at 13.5 d, the mesoderm gains a second inh ibitory activity, resulting in the irreversible loss of expression of HNF3 (Foxa2) and GATA factors in the endoderm and the absence of factors binding to their target sites in chromatin, The second inhibitory activity causes the endoderm to lose the potential to activate a liver gene, and this restr iction precedes the normal cytodifferentiation of the intestinal epithelium , In summary, two inhibitory interactions with mesoderm successively restri ct the developmental potential of the gut endoderm, leading to intestinal d ifferentiation. We also observed rare gut bud structures in midgestation em bryos that appear to represent murine examples of Meckel's Diverticulum, a congenital abnormality in human development, The absence of restrictive mes odermal interactions could explain how Meckel's diverticula express diverse non-intestinal, endoderm-derived cell types.