Reeler/disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2

Layering of neurons in the cerebral cortex and cerebellum requires Reelin, an extracellular matrix protein, and mammalian Disabled (mDab1), a cytosoli c protein that activates tyrosine kinases. Here, we report the requirement for two other proteins, cell surface receptors termed very low density lipo protein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Both rec eptors can bind mDab1 on their cytoplasmic tails and are expressed in corti cal and cerebellar layers adjacent to layers that express Reelin. mDab1 exp ression is upregulated in knockout mice that lack both VLDLR and ApoER2. In version of cortical layers and absence of cerebellar foliation in these ani mals precisely mimic the phenotype of mice lacking Reelin or mDab1. These f indings suggest that VLDLR and ApoER2 participate in transmitting the extra cellular Reelin signal to intracellular signaling processes initiated by mD ab1.