Interaction of reelin signaling and Lis1 in brain development

Amir H. Assadi; Guangcheng Zhang; Uwe Beffert; Robert S. McNeil; Amy L. Renfro; Sanyong Niu; Carlo C. Quattrocchi; Barbara A. Antalffy; Michael Sheldon; Dawna D. Armstrong; Anthony Wynshaw-Boris; Joachim Herz; Gabriella D'Arcangelo; Gary D. Clark

doi:10.1038/ng1257

Interaction of reelin signaling and Lis1 in brain development

Amir H. Assadi, Guangcheng Zhang, Uwe Beffert, Robert S. McNeil, Amy L. Renfro, Sanyong Niu, Carlo C. Quattrocchi, Barbara A. Antalffy, Michael Sheldon, Dawna D. Armstrong, Anthony Wynshaw-Boris, Joachim Herz, Gabriella D'Arcangelo, Gary D. Clark

Research output: Contribution to journal › Article › peer-review

190 Scopus citations

Abstract

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1^+/- mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. 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.

Original language	English (US)
Pages (from-to)	270-276
Number of pages	7
Journal	Nature genetics
Volume	35
Issue number	3
DOIs	https://doi.org/10.1038/ng1257
State	Published - Nov 2003

ASJC Scopus subject areas

Genetics

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@article{f4bc73db20fa40b39c90e981eeba6dbb,

title = "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 disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1+/- mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. 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.",

author = "Assadi, {Amir H.} and Guangcheng Zhang and Uwe Beffert and McNeil, {Robert S.} and Renfro, {Amy L.} and Sanyong Niu and Quattrocchi, {Carlo C.} and Antalffy, {Barbara A.} and Michael Sheldon and Armstrong, {Dawna D.} and Anthony Wynshaw-Boris and Joachim Herz and Gabriella D'Arcangelo and Clark, {Gary D.}",

note = "Funding Information: 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.",

year = "2003",

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doi = "10.1038/ng1257",

language = "English (US)",

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T1 - Interaction of reelin signaling and Lis1 in brain development

AU - Assadi, Amir H.

AU - Zhang, Guangcheng

AU - Beffert, Uwe

AU - McNeil, Robert S.

AU - Renfro, Amy L.

AU - Niu, Sanyong

AU - Quattrocchi, Carlo C.

AU - Antalffy, Barbara A.

AU - Sheldon, Michael

AU - Armstrong, Dawna D.

AU - Wynshaw-Boris, Anthony

AU - Herz, Joachim

AU - D'Arcangelo, Gabriella

AU - Clark, Gary D.

N1 - Funding Information: 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.

PY - 2003/11

Y1 - 2003/11

N2 - Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1+/- mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. 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.

AB - Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1+/- mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. 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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Interaction of reelin signaling and Lis1 in brain development

Abstract

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