Nature Genetics35, 270 - 276 (2003)
Published online: 26 October 2003; | doi:10.1038/ng1257
Interaction of reelin signaling and Lis1 in brain development
Amir H Assadi1, 2, 3, 12, Guangcheng Zhang1, 2, 12, Uwe Beffert4, Robert S McNeil1, 2, Amy L Renfro1, 2, 3, Sanyong Niu1, 2, Carlo C Quattrocchi1, 2, 5, Barbara A Antalffy6, Michael Sheldon2, 7, Dawna D Armstrong6, Anthony Wynshaw-Boris8, Joachim Herz4, Gabriella D'Arcangelo1, 2, 9, 10
& Gary D Clark1, 2, 9, 11
1
Cain Foundation Laboratories, Baylor College of Medicine, Houston, Texas 77030, USA.
2
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
3
University of Texas School of Public Health, Houston, Texas, USA.
4
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5
Program in Neuroscience, Università degli Studi di Brescia, Italy.
6
Department of Pathology, Baylor College of Medicine, Houston, Texas, USA.
7
Division of Hematology-Oncology and Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
8
Department of Pediatrics and Medicine, University of California San Diego, San Diego, California, USA.
9
Division of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
10
Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.
11
Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
12
These authors contributed equally to this work.
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.
