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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References
Reiner, O. et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein β-subunit-like repeats. Nature 364, 717–721 (1993).
D'Arcangelo, G. et al. A protein related to extracellular matrix proteins deleted in the mouse reeler. Nature 374, 719–723 (1995).
Hirotsune, S. et al. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat. Genet. 19, 333–339 (1998).
Trommsdorff, M. et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97, 689–701 (1999).
D'Arcangelo, G. et al. Reelin is a ligand for lipoprotein receptors. Neuron 24, 471–479 (1999).
Hiesberger, T. et al. Direct binding of reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of Disabled-1 and modulates Tau phosphorylation. Neuron 24, 481–489 (1999).
Howell, B.W., Hawkes, R., Soriano, P. & Cooper, J. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389, 733–737 (1997).
Sheldon, M. et al. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature 389, 730–733 (1997).
Howell, B.W., Herrick, T.M. & Cooper, J.A. Reelin-induced phosphorylation of Disabled 1 during neuronal positioning. Genes Dev. 13, 643–648 (1999).
Keshvara, L., Benhayon, D., Magdaleno, S. & Curran, T. Identification of Reelin-induced sites of tyrosyl phosphorylation on Disabled 1. J. Biol. Chem. 276, 16008–16014 (2001).
Sapir, T., Elbaum, M. & Reiner, O. Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit. EMBO J. 16, 6977–6984 (1998).
Luque, J.M., Morante-Oria, J. & Fairen, A. Localization of ApoER2, VLDLR and Dab1 in radial glia: groundwork for a new model of reelin action during cortical development. Brain Res. Dev. Brain Res. 140, 195–203 (2003).
Tramontin, A.D., Garcia-Verdugo, J.M., Lim, D.A. & Alvarez-Buylla, A. Postnatal development of radial glia and the ventricular zone (VZ): a continuum of the neural stem cell compartment. Cereb. Cortex 13, 580–587 (2003).
Clark, G.D., Mizuguchi, M., Antalffy, B., Barnes, J. & Armstrong, D. Predominant localization of the LIS family of gene products to Cajal-Retzius cells and ventricular neuroepithelium in the developing human cortex. J. Neuropathol. Exp. Neurol. 56, 1044–1052 (1997).
Miller, M.W. & Pitts, F.A. Neurotrophin receptors in the somatosensory cortex of the mature rat: co-localization of p75, trk, isoforms and c-neu. Brain Res. 852, 355–366 (2000).
Howell, B.W., Herrick, T.M., Hildebrand, J.D., Zhang, Y. & Cooper, J.A. Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development. Curr. Biol. 10, 877–885 (2000).
Bock, H.H. & Herz, J. Reelin activates Src family tyrosine kinases in neurons. Curr. Biol. 13, 18–26 (2003).
Sweeney, K.J., Clark, G.D., Prokscha, A., Dobyns, W.B. & Eichele, G. Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development. Mech. Dev. 92, 263–271 (2000).
Aumais, J.P. et al. NudC is highly expressed during neurogenesis and associates with Lis1 and the dynein motor at the leading edge of migrating neurons. J. Neurosci. 21, 1–7 (2001).
Brich, J. et al. Genetic modulation of tau phosphorylation in the mouse. J. Neurosci. 23, 187–192 (2003).
Kitagawa, M. et al. Direct association of LIS1, the lissencephaly gene product, with a mammalian homologue of a fungal nuclear distribution protein, rNUDE. FEBS Lett. 479, 57–62 (2000).
Efimov, V.P. & Morris, N.R. The LIS1-related NUDF protein of Aspergillus nidulans interacts with the coiled-coil domain of the NUDE/RO11 protein. J. Cell Biol. 150, 681–688 (2000).
Feng, Y. et al. LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron 28, 665–679 (2000).
Niethammer, M. et al. Nudel is a novel Cdk5 substrate that associates with Lis1 and cytoplasmic dynein. Neuron 28, 697–711 (2000).
Wynshaw-Boris, A. & Gambello, M.J. LIS1 and dynein motor function in neuronal migration and development. Genes Dev. 15, 639–651 (2001).
Sweeney, K.J., Prokscha, A. & Eichele, G. NudE-L, a novel Lis1-interacting protein, belongs to a family of vertebrate coiled-coil proteins. Mech. Dev. 101, 21–33 (2001).
D'Arcangelo, G., Miao, G.G. & Curran, T. Detection of the reelin breakpoint in reeler mice. Brain Res. Mol. Brain Res. 39, 234–236 (1996).
Bock, H.H. et al. PI3-Kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination. J. Biol. Chem. 278, 38772–38779 (2003).
Yan, W. et al. Previously uncharacterized roles of platelet-activating factor acetylhydrolase 1b complex in mouse spermatogenesis. Proc. Natl. Acad. Sci. USA 100, 7189–7194 (2003).
Sasaki, S. et al. A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. Neuron 28, 681–696 (2000).
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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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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DOI: https://doi.org/10.1038/ng1257
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