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FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry

Nature Neuroscience volume 17, pages 16931700 (2014) | Download Citation

Abstract

Deficiencies in fragile X mental retardation protein (FMRP) are the most common cause of inherited intellectual disability, fragile X syndrome (FXS), with symptoms manifesting during infancy and early childhood. Using a mouse model for FXS, we found that Fmrp regulates the positioning of neurons in the cortical plate during embryonic development, affecting their multipolar-to-bipolar transition (MBT). We identified N-cadherin, which is crucial for MBT, as an Fmrp-regulated target in embryonic brain. Furthermore, spontaneous network activity and high-resolution brain imaging revealed defects in the establishment of neuronal networks at very early developmental stages, further confirmed by an unbalanced excitatory and inhibitory network. Finally, reintroduction of Fmrp or N-cadherin in the embryo normalized early postnatal neuron activity. Our findings highlight the critical role of Fmrp in the developing cerebral cortex and might explain some of the clinical features observed in patients with FXS, such as alterations in synaptic communication and neuronal network connectivity.

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Acknowledgements

We are very grateful to E. Lemmens for administrative support, K. Jonckers, J. Royaert and I. Beheydt for their help and assistance with primary neurons and mouse colonies. We are thankful to T. Voets and S. Munck (coordinator of LiMoNe) for providing us excellent suggestions on the calcium imaging, P. Fazzari for helping with the synapses quantification, and M. Regoli for suggestions on the statistical analysis. G.L.F., N.D.-I. and M.A. were supported by grants FWO-G.0705.11 and FWO-G.0667.09 to C.B. T.A. was supported by a VIB grant to C.B. A.G. was partially supported by a VIB grant to C.B. and C.G.D. as well by an FWO grant (ZKC6058-00-W01) to A.G. U.H. and T.D. received financial support from the KUL-program financing IMIR (PF10/017). T.D. was supported by FWO-ZKC5858. R.M.M. J.D. and R.B.P. were supported by grants from FRAXA and Dutch Medical Research Council NWO VIDI (#917.10.372). G.L.F. is part of the Brain Train network (http://www.brain-train.nl/braintrain-program/partners/). This work was supported by grants from VIB, SAO, FWO-G.0705.11 and FWO-G.0667.09, and Associazione Italiana Sindrome X Fragile to C.B., and FWO-G0.666.10N, NEUROBRAINNET IAP 7/16, Flemish Methusalem grant, and Innovation Ingenio-Consolider, CSD2010-00045 to C.G.D.

Author information

Author notes

    • Giorgio La Fata
    •  & Rogier B Poorthuis

    Present address: Max Planck Institute for Brain Research, Frankfurt am Main, Germany (R.B.P.), DSM, Kaiseraugst, Switzerland (G.L.F.).

    • Giorgio La Fata
    • , Annette Gärtner
    •  & Nuria Domínguez-Iturza

    These authors contributed equally to this work.

Affiliations

  1. VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium.

    • Giorgio La Fata
    • , Annette Gärtner
    • , Nuria Domínguez-Iturza
    • , Michele Averna
    • , Tilmann Achsel
    • , Carlos G Dotti
    •  & Claudia Bagni
  2. Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium.

    • Giorgio La Fata
    • , Annette Gärtner
    • , Nuria Domínguez-Iturza
    • , Michele Averna
    • , Tilmann Achsel
    • , Carlos G Dotti
    •  & Claudia Bagni
  3. Biomedical MRI, KU Leuven, Leuven, Belgium.

    • Tom Dresselaers
    •  & Uwe Himmelreich
  4. Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, the Netherlands.

    • Julia Dawitz
    • , Rogier B Poorthuis
    •  & Rhiannon M Meredith
  5. Centro de Biología Molecular Severo Ochoa, Campus de la Universidad Autónoma de Madrid, Spain.

    • Carlos G Dotti
  6. Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

    • Claudia Bagni

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Contributions

G.L.F., A.G., C.G.D., T.A. and C.B. designed the experiments and wrote the manuscript. A.G. and C.B. supervised the project. G.L.F. and A.G. performed a major part of the experiments and analyzed the data. N.D.-I. contributed substantially to the experiments and data analysis during the entire review process. M.A. contributed to some experiments. T.D. and U.H. performed and analyzed the MRI scans. R.M.M., J.D. and R.B.P. performed and analyzed the initial calcium imaging experiments and A.G., N.D.-I. and T.A. performed and analyzed the electroporation with calcium imaging experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Claudia Bagni.

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https://doi.org/10.1038/nn.3870

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