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Differential interaction of the Pafah1b alpha subunits with the Reelin transducer Dab1.

ABSTRACT: The Reelin signaling pathway controls radial neuronal migration and maturation in the developing brain. The platelet activating factor (PAF) acetyl hydrolase 1b (Pafah1b) complex is also involved in multiple aspects of brain development. We previously showed that the Reelin pathway and the Pafah1b complex interact genetically and biochemically. Lis1, the regulatory subunit of Pafah1b interacts with phosphoDab1, an essential mediator of Reelin signaling. Compound mutants carrying mutations in both, the Reelin pathway and Lis1 exhibit hydrocephalus, a phenotype that is suppressed by mutations in the gene encoding the Alpha2 subunit of Pafah1b. This subunit, like the Alpha1 catalytic subunit of Pafah1b also binds the Reelin receptor VLDLR. Here we investigated the molecular interactions of the Pafah1b catalytic subunits with Dab1. We found that Alpha2 coprecipitates with Dab1 from brain extracts of normal and reeler mutant mice lacking Reelin, and from cell-free extracts containing normal or a phosphorylation mutant form of Dab1, suggesting that Dab1 phosphorylation is not necessary for binding to Alpha2. This interaction is specific for Alpha2 and not Alpha1, and depends on a unique tyrosine residue of Alpha2. Biochemical assays using mutant mice lacking Alpha2 further demonstrated that this subunit is not required for Reelin-induced Dab1 phosphorylation. However, increasing amounts of Alpha2 in a cell-free system disrupted the formation of Dab1-Lis1 complexes without affecting the association of Dab1 with VLDLR. Our data suggest that the Alpha2 subunit may play a modulatory role in the formation of protein complexes that affect brain development and hydrocephalus.

SUBMITTER: Zhang G

PROVIDER: S-EPMC2673792 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Differential interaction of the Pafah1b alpha subunits with the Reelin transducer Dab1.

Zhang Guangcheng G Assadi Amir H AH Roceri Mila M Clark Gary D GD D'Arcangelo Gabriella G

Brain research 20090309

The Reelin signaling pathway controls radial neuronal migration and maturation in the developing brain. The platelet activating factor (PAF) acetyl hydrolase 1b (Pafah1b) complex is also involved in multiple aspects of brain development. We previously showed that the Reelin pathway and the Pafah1b complex interact genetically and biochemically. Lis1, the regulatory subunit of Pafah1b interacts with phosphoDab1, an essential mediator of Reelin signaling. Compound mutants carrying mutations in bot ...[more]

PMID: 19272360

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Project description:BackgroundThe secreted ligand Reelin is believed to regulate the translocation of prospective layer 6 (L6) neocortical neurons into the preplate, a loose layer of pioneer neurons that overlies the ventricular zone. Recent studies have also suggested that Reelin controls neuronal orientation and polarized dendritic growth during this period of early cortical development. To explicitly characterize and quantify how Reelin controls this critical aspect of neurite initiation and growth we used a new ex utero explant model of early cortical development to selectively label a subset of L6 cortical neurons for complete 3-D reconstruction.ResultsThe total neurite arbor sizes of neurons in Reelin-deficient (reeler mutant) and Dab1-deficient (Reelin-non-responsive scrambler mutant) cortices were quantified and unexpectedly were not different than control arbor lengths (p = 0.51). For each mutant, however, arbor organization was markedly different: mutant neurons manifested more primary processes (neurites emitted directly from the soma) than wild type, and these neurites were longer and displayed less branching. Reeler and scrambler mutant neurites extended tangentially rather than radially, and the Golgi apparatus that normally invests the apical neurite was compact in both reeler and scrambler mutants. Mutant cortices also exhibited a neurite "exclusion zone" which was relatively devoid of L6 neuron neurites and extended at least 15 μm beneath the pial surface, an area corresponding to the marginal zone (MZ) in the wild type explants. The presence of an exclusion zone was also indicated in the orientation of mutant primary neurite and neuronal somata, which failed to adopt angles within ~20˚ of the radial line to the pial surface. Injection of recombinant Reelin to reeler, but not scrambler, mutant cortices fully rescued soma orientation, Golgi organization, and dendritic projection defects within four hrs.ConclusionsThese findings indicate Reelin promotes directional dendritic growth into the MZ, an otherwise exclusionary zone for L6 neurites.

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Differential interaction of the Pafah1b alpha subunits with the Reelin transducer Dab1.

Publications

Differential interaction of the Pafah1b alpha subunits with the Reelin transducer Dab1.

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