Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development

Background: The extracellular protein Rein controls neuronal migrations in parts of the cortex, hippocampus and cerebellum. In vivo, absence of Rein c orrelates with up-regulation of the docking protein Dab1 and decreased Dab1 tyrosine phosphorylation. Loss of the Rein receptor proteins, apolipoprote in receptor 2 and very low density lipoprotein receptor. results in a Rein- like phenotype accompanied by increased Dab1 protein expression, Complete l oss of Dab1, however, recapitulates the Rein phenotype. Results: To determine whether Dab1 tyrosine phosphorylation affects Dab1 pr otein expression and positioning of embryonic neurons, we have identified D ab1 tyrosine phosphorylation sites. We then generated mice in which the Dab 1 protein had all the potential tyrosine phosphorylation sites mutated. Thi s mutant protein is not tyrosine phosphorylated during brain development an d is not upregulated to the extent observed in the Rein or the apoER2 and V LDLR receptor mutants. Animals expressing the non-phosphorylated Dab1 prote in have a phenotype similar to the dab1-null mutant. Conclusions: Dab1 is downregulated by the Rein signal in neurons in the abs ence of tyrosine phosphorylation. Dab1 tyrosine phosphorylation sites and n ot downregulation of Dab1 protein are required for Rein signaling. (C) 2000 Elsevier Science Ltd. All rights reserved.