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A dual shaping mechanism for postsynaptic ephrin-B3 as a receptor that sculpts dendrites and synapses

Nature Neuroscience volume 14, pages 1421–1429 (2011)Cite this article

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Abstract

As the neural network becomes wired, postsynaptic signaling molecules are thought to control the growth of dendrites and synapses. However, how these molecules are coordinated to sculpt postsynaptic structures is less well understood. We find that ephrin-B3, a transmembrane ligand for Eph receptors, functions postsynaptically as a receptor to transduce reverse signals into developing dendrites of mouse hippocampal neurons. Both tyrosine phosphorylation–dependent GRB4 SH2/SH3 adaptor-mediated signals and PSD-95–discs large–zona occludens-1 (PDZ) domain–dependent signals are required for inhibition of dendrite branching, whereas only PDZ interactions are necessary for spine formation and excitatory synaptic function. PICK1 and syntenin, two PDZ domain proteins, participate with ephrin-B3 in these postsynaptic activities. PICK1 has a specific role in spine and synapse formation, and syntenin promotes both dendrite pruning and synapse formation to build postsynaptic structures that are essential for neural circuits. The study thus dissects ephrin-B reverse signaling into three distinct intracellular pathways and protein–protein interactions that mediate the maturation of postsynaptic neurons.

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Figure 1: eB3 is required for dendrite pruning and spine formation in hippocampal CA1 neurons.
Figure 2: eB3 is required and sufficient for excitatory synaptic function in hippocampal CA1 neurons.
Figure 3: eB3 tyrosine phosphorylation and PDZ binding are differentially required for dendrite morphogenesis and synaptic function.
Figure 4: PDZ binding of eB3 are required for synaptic function.
Figure 5: PICK1 and syntenin mediate eB3 reverse signaling through PDZ binding to control spine and synapse formation and synaptic function.
Figure 6: GRB4, PICK1 and syntenin mediated distinct reverse signaling to prune primary dendrites in cultured hippocampal neurons.
Figure 7: Association of eB3-PICK1 or eB3-Syn with downstream signaling molecules.

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Acknowledgements

We thank J. Sanes (Harvard University) for Thy1-GFP-M transgenic mice, G. Chenaux (University of Texas Southwestern Medical Center) for Efnb26FΔV mice, H. Zeng (Allen Institute for Brain Science) for CAGG-tdTomato transgenic mice, A. McMahon (Harvard University) for CAGG-Cre-ER™ transgenic mice, A. Bergemann (Mount Sinai Medical Center) for eB3 cDNA pEXPRmELF3, I.M. Ethell (University of California, Riverside) for HA-syndecan-2 plasmid, I. Bezprozvanny, B. Miller and A. Patel (University of Texas Southwestern) for electrophysiological recording setups and assistance with electrophysiology, and F. Sprouse (University of Texas Southwestern Medical Center) for genotyping. This research was supported by a US National Institutes of Health grant (R01 MH66332) to M.H.

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Authors and Affiliations

  1. Department of Developmental Biology and Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Nan-Jie Xu & Mark Henkemeyer

  2. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Suya Sun

  3. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Jay R Gibson

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  1. Nan-Jie Xu
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Contributions

N.-J.X. generated Ephb3neo, Ephb33F, Ephb35F, Efnb3ΔV and Efnb33FΔV knock-in mice. N.-J.X. and S.S. performed the experiments. J.R.G. supervised the electrophysiological recording in brain slides. N.-J.X. and M.H. designed experiments and wrote the manuscript.

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Correspondence to Mark Henkemeyer.

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Xu, NJ., Sun, S., Gibson, J. et al. A dual shaping mechanism for postsynaptic ephrin-B3 as a receptor that sculpts dendrites and synapses. Nat Neurosci 14, 1421–1429 (2011). https://doi.org/10.1038/nn.2931

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