The significance of blood vessels in organogenesis and cadherins in exploratory behaviour

Sammanfattning: Organogenesis of epithelial organs requires interaction between epithelial andmesenchymal tissues. In pancreas development three different mesenchymal derivedstructures, the notochord, the endothelial cells and the splanchnic mesenchyme inducespecification, growth and further differentiation of the pancreatic epithelium.Previously, N-cadherin deficient embryos were shown to suffer from agenesis ofthe dorsal pancreas due to apoptosis of the pancreatic mesenchyme. However, byexpressing N- and E-cadherin selectively in the heart, the pancreatic phenotype was shownto be secondary to the non-functional cardiac- and vascular-system in N-cadherin-/-embryos. In addition, plasma from wild-type embryos rescued dorsal pancreas formationin N-cadherin-/- explants, suggesting factors from the circulation to be involved inpancreatic ontogeny. Recently, sphingosine-1-phosphate receptor-1 was shown to berequired for proper recruitment of vascular smooth muscle cells to the aortic wall.Vascular smooth muscle cells and dorsal pancreatic mesenchyme may originate from acommon cellular source, the splanchnic mesenchyme, and migrate to endothelial andepithelial cells, respectively, in close vicinity, suggesting that they may be regulated bysimilar developmental regulatory pathways. Consequently, the ligand, a blood bornesphingolipid metabolite, sphingosine-1-phosphate, may be involved in pancreas ontogenyas well. Indeed, the sphingosine-1-phosphate rescued dorsal pancreas in N-cadherin-/-explants by inducing proliferation of the mesenchyme. To clarify the requirement forsphingosine-1-phosphate in pancreas development, embryos deficient in sphingosine-1-phosphate receptor-1 were analysed. Whereas initial development of dorsal and ventralpancreas proceeded normally, obvious morphological changes of the dorsal pancreaticepithelium were observed at later stages, indicating defective mesenchymal-to-epithelialinteractions. The sphingosine-1-phosphate receptor-1 was mainly expressed in endothelialcells, suggesting that sphingosine-1-phosphate signals to the mesenchyme via endothelialcells. Altogether, we show for the first time that vascular function and spingosine-1-phosphate-mediating signalling regulate pancreas ontogeny by inducing mesenchymal-toepithelialsignalling.Cadherins are cell-to-cell adhesion molecules localised at the synaptic junctions,mediating synaptogenesis and neuronal path finding during development. By using theCre/loxP-system, an in vivo model was established where a dominant negative cadherinwas expressed selectively in the neurons of the central nervous system in the adult mouse.Cadherins role in neural plasticity and behaviour was analysed and demonstrated normalsynaptic transmission, long term potentiation, spatial learning and anxiety responses, whilerearing behaviour, a component in exploration was significantly reduced. Datademonstrate, for the first time, a functional role for cadherins in modifying rearing andexploratory behaviour in vivo.