Instructive roles of the vasculature during neuronal arborization and spine morphogenesis

• Applicant: Professorin Dr. Amparo Acker-Palmer
• Subject Area: Developmental Neurobiology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269353708

Proper cellular communication between the different cell types in the brain is fundamental for brain function, however little is known about the signalling effectors that are used for such trans-cellular signalling. The main focus of our work is to delineate the molecular pathways that govern the inter-cellular communication to understand basic mechanisms of brain development, function and dysfunction. In the previous funding period, we analysed the role of the VEGF/VEGFR2 axis in the development of the hippocampus. We found that neuronal VEGFR2 instructs the dendritic branching and spine formation in CA3 pyramidal hippocampal neurons through a conserved mechanism similar to its role during vascular morphogenesis. We sought for the cellular source of VEGF and we found that autocrine secretion of VEGF by neurons is dispensable for dendritogenesis and spine formation in the developing hippocampus. However, paracrine VEGF secreted by astrocytes and vessels seems to differentially modulate the function of VEGFR2 in the different neuronal compartments. Thus, neuronal VEGFR2 regulates the development of the dendritic arbors of the hippocampus upon vascular derived VEGF signals, showing that the endothelial cells promote the formation of the neuronal circuits that ultimately will be fundamental for learning and memory processes. In the next funding period, we aim to study the vascularization of the cerebellum and the role of the vasculature in controlling the arborization of Purkinje cells, the migration of granular cells and the organization of the Bergmann glia. Additionally, we will analyse the functional consequences of the morphological alterations on single cells and on neuronal network in the cerebellum, with special focus on Purkinje cells and granule cells. We will use patch-clamp electrophysiology and will also perform behavioural experiments to investigate whether specific cerebellar functions are disrupted in the vascular signalling mutants. Moreover, we found that specific zebrafish mutants expose retinal ganglion cells (RGCs) axonal misguidance in targeting the upper layers of the optic tectum (OT) and consequently an altered visual behaviour. We will continue to analyse RGCs lamination and arborization of the zebrafish OT and decipher the possible interacting partners involved in the wiring process of the RGCs axons.

• DFG Programme: Research Units
• Subproject of: FOR 2325: Interactions at the Neurovascular Interface