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Cell-cell interactions at the neurovascular interface

Periodic Reporting for period 4 - NEUROVESSEL (Cell-cell interactions at the neurovascular interface)

Reporting period: 2020-07-01 to 2021-06-30

The coordinated orchestration of cell movements is a vital process for assembling functional structures. In recent years we have learned a simplifying lesson: organ development is governed by a limited set of conserved cell-to-cell communication signaling pathways repeatedly used in different contexts.Particularly fascinating is the parallelism between the vascular and nervous systems. My lab has been working for more than a decade on the molecular and functional parallelism between nervous and vascular system development and plasticity. Although it is clear that cellular communication between the different cells in the brain is fundamental for brain function, very little is known about the signaling effectors that are used for such trans-cellular signaling. Molecular pathways involved in the crosstalk between vessels and neuronal cells are slowly emerging. How this crosstalk signaling is integrated at the interface of the different cellular players (neurons, endothelial cells, glial cells) for proper brain development and function is still poorly understood. Here I propose to delineate the molecular pathways that govern such communication in order to understand basic mechanisms of brain development, function and dysfunction. Using a combination of state-of-the-art inducible and cell type-specific genetics, both in mouse and zebrafish, together with high-resolution light microscopy and multi-photon live imaging we will examine the cell-context dependent integration of signaling pathways in building up proper neuronal/glial structures and functional networks. We will use advanced ultra-structural analysis using serial block-face electron microscopy (SBEM) to obtain high-resolution maps of cortical structures. Functionally, we will characterize the integration of vascular/glial/neuronal signals during cortical neuronal migration, arborization, synaptic connectivity, higher-order integrative cortical function and behavior-related plasticity in vivo.
The central nervous system (CNS) constitutes an intricate network of different cell types that intercommunicate to develop and to maintain the cerebral function. Interestingly, the nervous and the vascular system share several morphological characteristics as well as their branching pattern is governed by common guidance cues. We have postulated in our proposal that the molecular signals that instruct the vascular and neuronal network establishment might also be responsible for orchestrating the cell-to-cell communication between the different constituents of the CNS. In line with this hypothesis, we proposed several aims in order to investigate the involvement of different molecular players in the neuron-glia-vascular crosstalk and to analyse their impact on the homeostasis of brain function. We have generated different mutant lines in mouse and zebrafish and we are currently analysing the neurovascular interactions at the molecular and functions level.
We expect that at the end of this project the results generated will allow us to understand the basic molecular mechanisms that lead to proper structure and function at the neurovascular interface during development and how these mechanisms are important for brain homeostasis to maintain mental health.
Interaction of glia (blue), neurons (green) and vessels (red) in the brain