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Interaction of reelin signaling and Lis1 in brain development

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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Figure 1: Progressive hydrocephalus in combined mutants caused by periventricular and aqueductal defects.
Figure 2: Enhanced hippocampal and cortical malformations in Pafah1b1 Dab1 compound heterozygotes.
Figure 3: Biochemical interaction of Dab1 with Lis1.
Figure 4: Reelin-induced tyrosine phosphorylation of Dab1 is required for Lis1-Dab1 binding.
Figure 5: Cellular colocalization of Lis1 and Dab1.
Figure 6: Schematic summary of reelin and Lis1 signaling.

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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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Correspondence to Gary 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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