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Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration

Nature volume 472, pages 356–360 (2011)Cite this article

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A Corrigendum to this article was published on 28 September 2011

Abstract

Coordinated migration of neurons in the developing and adult brain is essential for its proper function. The secreted glycoprotein Reelin (also known as RELN) guides migration of neurons by binding to two lipoprotein receptors, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2, also known as LRP8)1. Loss of Reelin function in humans results in the severe developmental disorder lissencephaly2 and it has also been associated with other neurological disorders such as epilepsy, schizophrenia and Alzheimer’s disease3. The molecular mechanisms by which Reelin activates its receptors and controls cellular functions are largely unknown. Here we show that the neuronal guidance cues ephrin B proteins are essential for Reelin signalling during the development of laminated structures in the brain. We show that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln+/−; Efnb3−/− or Reln+/−; Efnb2−/−) and triple ephrin B1, B2, B3 knockouts show neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse. Mechanistically, we show that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1 which is necessary for Reelin signalling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Together, our results identify ephrin Bs as essential components of the Reelin receptor/signalling pathway to control neuronal migration during the development of the nervous system.

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Figure 1: Ephrin B3 and ephrin B2 deficiency differentially phenocopy reeler -like defects.
Figure 2: Ephrin B1, B2, B3 triple mutants show a reeler -like phenotype.
Figure 3: Ephrin B2 and ephrin B3 ligands bind to Reelin and cluster VLDLR and ApoER2 signalling machinery.
Figure 4: Ephrin Bs are required for Reelin signalling in vivo and rescue the reeler defects.

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Acknowledgements

We would like to thank R. Klein for the ephrin B2lox/lox and ephrin B1lox/lox mice, N. Gale for the ephrin B3−/− mouse, J. Herz for the ApoER2−/− mouse, M. Goetz for 293-cells expressing Reelin or GFP, I. Segura for help with the ephrin B triple mutants, U. Bauer, O. Yildiz, C. Saygi, F. Kasikci, F. Voss and K. Happich for technical support, K. Hong and A. Griciuc for early contributions to this project, M. Frotscher for helpful discussions and I. Dikic and T. Acker for critically reading the manuscript. We acknowledge the Max Planck Institute of Neurobiology in Martinsried (Germany) for support and the use of equipment and animal facilities in the early stages of this project. This work was supported by grants from the Deutsche Forschungsgemeinschaft (AC180/2-1, 2-2 to A.A.-P.) and the Clusters of Excellence “Macromolecular Complexes (CEF)” (EXC115) and ECCPS (EXC147) at the University Frankfurt.

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  1. Alexander Weiss & Katja Burk

    Present address: Present addresses: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 1078, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada (A.W.); IBDML-UMR6216-CNRS, Case 907- Parc Scientifique de Luminy, 13288 Marseille Cedex 9, France (K.B.).,

Authors and Affiliations

  1. Frankfurt Institute for Molecular Life Sciences (FMLS) and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438, Frankfurt am Main, Germany

    Aycan Sentürk, Sylvia Pfennig, Alexander Weiss, Katja Burk & Amparo Acker-Palmer

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Contributions

A.S. designed experiments and performed all the phenotypic characterization of the mouse mutants, the cortical neuron culture, organotypic slice culture rescue experiments and electroporation of cerebellar acute slice cultures. S.P. performed some of the neuronal culture experiments, organotypic slice culture rescue experiments and the biochemistry. A.W. and K.B. performed biochemistry for panels d and a in Fig. 4. A.A.-P. performed the initial biochemistry on the binding of ephrin B ligands to Reelin, designed experiments, interpreted results and wrote the manuscript.

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Correspondence to Amparo Acker-Palmer.

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Sentürk, A., Pfennig, S., Weiss, A. et al. Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration. Nature 472, 356–360 (2011). https://doi.org/10.1038/nature09874

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