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Elife. 2019 Dec 23;8. pii: e49818. doi: 10.7554/eLife.49818.

VEGF/VEGFR2 signaling regulates hippocampal axon branching during development.

Author information

1
Biochemistry Center (BZH), University of Heidelberg, Heidelberg, Germany.
2
European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
3
Institute for Transfusion Medicine and Immunology, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
4
Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt am Main, Germany.
5
Neurovascular Interface group, Max Planck Institute for Brain Research, Frankfurt am Main, Germany.
6
Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt am Main, Germany.
7
Department of Synaptic Plasticity, Max Planck Institute for Brain Research, Frankfurt am Main, Germany.
8
Imaging Facility, Max Planck Institute for Brain Research, Frankfurt am Main, Germany.
9
Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
#
Contributed equally

Abstract

Axon branching is crucial for proper formation of neuronal networks. Although originally identified as an angiogenic factor, VEGF also signals directly to neurons to regulate their development and function. Here we show that VEGF and its receptor VEGFR2 (also known as KDR or FLK1) are expressed in mouse hippocampal neurons during development, with VEGFR2 locally expressed in the CA3 region. Activation of VEGF/VEGFR2 signaling in isolated hippocampal neurons results in increased axon branching. Remarkably, inactivation of VEGFR2 also results in increased axon branching in vitro and in vivo. The increased CA3 axon branching is not productive as these axons are less mature and form less functional synapses with CA1 neurons. Mechanistically, while VEGF promotes the growth of formed branches without affecting filopodia formation, loss of VEGFR2 increases the number of filopodia and enhances the growth rate of new branches. Thus, a controlled VEGF/VEGFR2 signaling is required for proper CA3 hippocampal axon branching during mouse hippocampus development.

KEYWORDS:

VEGF; VEGFR2; axon branching; develomental neuroscience; developmental biology; hippocampus; mouse; neuro-vascular link

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