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A Fragment of Adhesion Molecule L1 Binds to Nuclear Receptors to Regulate Synaptic Plasticity and Motor Coordination

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Abstract

Proteolytic cleavage of the neuronal isoform of the murine cell adhesion molecule L1, triggered by stimulation of the cognate L1-dependent signaling pathways, results in the generation and nuclear import of an L1 fragment that contains the intracellular domain, the transmembrane domain, and part of the extracellular domain. Here, we show that the LXXLL and FXXLF motifs in the extracellular and transmembrane domain of this L1 fragment mediate the interaction with the nuclear estrogen receptors α (ERα) and β (ERβ), peroxisome proliferator-activated receptor γ (PPARγ), and retinoid X receptor β (RXRβ). Mutations of the LXXLL motif in the transmembrane domain and of the FXXLF motif in the extracellular domain disturb the interaction of the L1 fragment with these nuclear receptors and, when introduced by viral transduction into mouse embryos in utero, result in impaired motor coordination, learning and memory, as well as synaptic connectivity in the cerebellum, in adulthood. These impairments are similar to those observed in the L1-deficient mouse. Our findings suggest that the interplay of nuclear L1 and distinct nuclear receptors is associated with synaptic contact formation and plasticity.

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Acknowledgements

We are grateful to Eva Kronberg for the excellent animal care and to Ute Bork and Dagmar Drexler for the excellent technical assistance.

Funding

D.L. is supported by a FFM fellowship of the Medical Faculty, University Medical Center Hamburg-Eppendorf. D.L. is grateful for the support by the Hertie Foundation. M.H. is supported by the Egyptian Cultural Bureau Berlin, Egyptian Ministry of Higher Education, and the Egyptian Missions Sector. M.S. is grateful for the support by the Li Kashing Foundation at Shantou University Medical College.

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Authors and Affiliations

  1. Arbeitsgruppe für Biosynthese Neuraler Strukturen, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Kristina Kraus, Ralf Kleene, Hardeep Kataria, Gabriele Loers & David Lutz

  2. Institut für Strukturelle Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Melad Henis, Ahmed Sharaf & David Lutz

  3. Department of Anatomy and Histology, Faculty of Veterinary Medicine, Assiut University, Assiut, 71526, Egypt

    Melad Henis

  4. Vector Core Unit, Institut für Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Ingke Braren

  5. Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt

    Ahmed Sharaf

  6. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854, USA

    Melitta Schachner

  7. Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong, 515041, China

    Melitta Schachner

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  1. Kristina Kraus
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  2. Ralf Kleene
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  3. Melad Henis
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  4. Ingke Braren
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  5. Hardeep Kataria
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  6. Ahmed Sharaf
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  7. Gabriele Loers
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  8. Melitta Schachner
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  9. David Lutz
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Corresponding authors

Correspondence to Melitta Schachner or David Lutz.

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Experiments were carried out and the manuscript was prepared following the ARRIVE guidelines for animal research [39].

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The authors declare that they have no conflict of interest.

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Kraus, K., Kleene, R., Henis, M. et al. A Fragment of Adhesion Molecule L1 Binds to Nuclear Receptors to Regulate Synaptic Plasticity and Motor Coordination. Mol Neurobiol 55, 7164–7178 (2018). https://doi.org/10.1007/s12035-018-0901-7

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  • DOI: https://doi.org/10.1007/s12035-018-0901-7

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