A fascinating characteristic of the anatomy of the vascular system is that blood vessels exhibit a high similarity in their branching pattern and often a remarkable alignment to nerve fibers. This parallel wiring of the vascular and the nervous system might reflect its mutual dependence and also might indicate mutual guidance phenomena, with vessels providing the signals and the scaffold for growing nerves and nerves secreting angiogenic cues to guide developing vessels.The main goal of this project is to elucidate the molecular mechanisms by which blood vessels may lead the neurons to achieve proper positioning at the developing brain and the molecular cues that are involved in this guidance process. More precisely, we will explore the role of the vasculature on neuronal migration via the Reelin pathway. Reelin is a large, secreted glycoprotein that acts as a guidance molecule on migrating neurons to regulate their proper positioning during brain development. Reelin binds to two lipoprotein receptors, VLDLR and ApoER2, and induces the phosphorylation of the adaptor protein Dab1. Mice that lack Reelin expression (Reeler mice) exhibit severe neuropathological abnormalities. Our preliminary data identifies Reelin as an angiogenic factor and is the basis for an exciting project that aims at studying Reelin as a putative angioneurin, a novel concept of molecules that affects both neural and vascular cell processes. To explore this we will design an endothelial specific Dab1 null mice (Tie2Dab1-/-) to study the loss of function of Reelin selectively on endothelial cells and we will study the contribution of the vasculature to the nervous system defects in the reeler phenotype. This project will contribute to elucidate the molecular basis of the neurovascular link in health and disease and further contribute to the emerging research on the neurovascular development.