Description:
Intestinal cylindrical growth peaks in mice a few weeks after birth, simultaneously withcrypt fission activity. It nearly stops after weaning and cannot be reactivated later. Transgenic mice expressing Cd97/Adgre5 in the intestinal epithelium develop a mega-intestine with normal microscopicmorphology in adult mice. Here, we demonstrate premature intestinal differentiation in Cd97/Adgre5transgenic mice at both the cellular and molecular levels until postnatal day 14. Subsequently, thegrowth of the intestinal epithelium becomes activated and its maturation suppressed. These changesare paralleled by postnatal regulation of growth factors and by an increased expression of secretorycell markers, suggesting growth activation of non-epithelial tissue layers as the origin of enforcedtissue growth. To understand postnatal intestinal growth mechanistically, we study epithelial fatedecisions during this period with the use of a 3D individual cell-based computer model. In the model,the expansion of the intestinal stem cell (SC) population, a prerequisite for crypt fission, is largelyindependent of the tissue growth rate and is therefore not spontaneously adaptive. Accordingly,the model suggests that, besides the growth activation of non-epithelial tissue layers, the formationof a mega-intestine requires a released growth control in the epithelium, enabling accelerated SCexpansion. The similar intestinal morphology in Cd97/Adgre5 transgenic and wild type mice indicates a synchronization of tissue growth and SC expansion, likely by a crypt density-controlledcontact inhibition of growth of intestinal SC proliferation. The formation of a mega-intestine withnormal microscopic morphology turns out to originate in changes of autonomous and conditionalspecification of the intestinal cell fate induced by the activation of Cd97/Adgre5.