VEGF/VEGFR2 signaling regulates hippocampal axon branching during development
Robert Luck,
Severino Urban,
Andromachi Karakatsani,
Eva Harde,
Sivakumar Sambandan,
LaShae Nicholson,
Silke Haverkamp,
Rebecca Mann,
Ana Martin-Villalba,
Erin Margaret Schuman,
Amparo Acker-Palmer,
Carmen Ruiz de Almodóvar
Affiliations
Robert Luck
Biochemistry Center (BZH), University of Heidelberg, Heidelberg, Germany; European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Institute for Transfusion Medicine and Immunology, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany
Severino Urban
Biochemistry Center (BZH), University of Heidelberg, Heidelberg, Germany
Andromachi Karakatsani
Biochemistry Center (BZH), University of Heidelberg, Heidelberg, Germany; European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Institute for Transfusion Medicine and Immunology, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany
Eva Harde
Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt am Main, Germany; Neurovascular Interface group, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt am Main, Germany
Sivakumar Sambandan
Department of Synaptic Plasticity, Max Planck Institute for Brain Research, Frankfurt am Main, Germany
LaShae Nicholson
Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt am Main, Germany; Neurovascular Interface group, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt am Main, Germany
Silke Haverkamp
Imaging Facility, Max Planck Institute for Brain Research, Frankfurt am Main, Germany
Rebecca Mann
Biochemistry Center (BZH), University of Heidelberg, Heidelberg, Germany
Department of Synaptic Plasticity, Max Planck Institute for Brain Research, Frankfurt am Main, Germany
Amparo Acker-Palmer
Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt am Main, Germany; Neurovascular Interface group, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt am Main, Germany
Biochemistry Center (BZH), University of Heidelberg, Heidelberg, Germany; European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Institute for Transfusion Medicine and Immunology, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany
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.
