Interaction of reelin signaling and Lis1 in brain development (original) (raw)

Nature Genetics volume 35, pages 270–276 (2003)Cite this article

Abstract

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder1. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers2. Pafah1b1 +/− mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal3. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors4,5,6, thereby phosphorylating the Dab1 signaling molecule7,8,9,10. Lis1 associates with microtubules and modulates neuronal migration11. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.

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Acknowledgements

The authors thank C. Walsh, G. Eichele and H. Zoghbi for critical reading of the manuscript; T. Curran for the gift of many reagents; J. Hayes and W.-L. Niu for technical assistance. This study was supported by grants from the US National Institutes of Health (to G.D.C., G.D., A.W.-B., J.H.), the Alzheimer Association and the Humboldt Foundation (to J.H.). U.B. was a fellow of the Human Frontier Science Program during part of this work.

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Author notes

  1. Amir H Assadi and Guangcheng Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, Texas, USA
    Amir H Assadi, Guangcheng Zhang, Robert S McNeil, Amy L Renfro, Sanyong Niu, Carlo C Quattrocchi, Gabriella D'Arcangelo & Gary D Clark
  2. Department of Pediatrics, Baylor College of Medicine, Houston, 77030, Texas, USA
    Amir H Assadi, Guangcheng Zhang, Robert S McNeil, Amy L Renfro, Sanyong Niu, Carlo C Quattrocchi, Michael Sheldon, Gabriella D'Arcangelo & Gary D Clark
  3. University of Texas School of Public Health, Houston, Texas, USA
    Amir H Assadi & Amy L Renfro
  4. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Uwe Beffert & Joachim Herz
  5. Program in Neuroscience, Università degli Studi di Brescia, Italy
    Carlo C Quattrocchi
  6. Department of Pathology, Baylor College of Medicine, Houston, Texas, USA
    Barbara A Antalffy & Dawna D Armstrong
  7. Division of Hematology-Oncology and Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA
    Michael Sheldon
  8. Department of Pediatrics and Medicine, University of California San Diego, San Diego, California, USA
    Anthony Wynshaw-Boris
  9. Division of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
    Gabriella D'Arcangelo & Gary D Clark
  10. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA
    Gabriella D'Arcangelo
  11. Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
    Gary D Clark

Authors

  1. Amir H Assadi
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  2. Guangcheng Zhang
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  3. Uwe Beffert
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  4. Robert S McNeil
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  5. Amy L Renfro
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  6. Sanyong Niu
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  7. Carlo C Quattrocchi
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  8. Barbara A Antalffy
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  9. Michael Sheldon
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  10. Dawna D Armstrong
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  11. Anthony Wynshaw-Boris
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  12. Joachim Herz
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  13. Gabriella D'Arcangelo
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  14. Gary D Clark
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Corresponding author

Correspondence toGary D Clark.

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Assadi, A., Zhang, G., Beffert, U. et al. Interaction of reelin signaling and Lis1 in brain development.Nat Genet 35, 270–276 (2003). https://doi.org/10.1038/ng1257

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