Reeler/Disabled-like Disruption of Neuronal Migration in Knockout Mice Lacking the VLDL Receptor and ApoE Receptor

D'Arcangelo, 1998). In the cortex, this modular protein is * Department of Molecular Genetics either associated with the extracellular matrix or with † Department of Pathology the surface of a special class of neurons that produce ‡ Department of Biochemistry it in the outermost layer just beneath the pial surface. As a result, in these mice A-1030 Vienna migratory neurons apparently do not receive a critical Austria cue that informs them of their position, leading to an inversion of the cortical layers. These layers normally form from the inside out, with later-born neurons migrat-Summary ing past older ones to form progressively more superficial , and thus younger, layers of the neocortex. In the Layering of neurons in the cerebral cortex and cerebel-cerebellum, Reelin is required for the Purkinje cells to lum requires Reelin, an extracellular matrix protein, migrate outward, where they form a well-defined cortical and mammalian Disabled (mDab1), a cytosolic protein plate through which postmitotic granule cells migrate that activates tyrosine kinases. Here, we report the inward to form the internal granular layer (Miyata et al., requirement for two other proteins, cell surface recep-1997; Komuro and Rakic, 1998; Wechsler-Reya and tors termed very low density lipoprotein receptor Scott, 1999). Both of these laminated structures do not (VLDLR) and apolipoprotein E receptor 2 (ApoER2). form in the reeler mouse. Both receptors can bind mDab1 on their cytoplasmic The cytoplasmic adaptor protein mDab1 is related to tails and are expressed in cortical and cerebellar layers the Drosophila disabled gene product. It is predomi-adjacent to layers that express Reelin. mDab1 expres-nantly expressed in neurons and has been shown to sion is upregulated in knockout mice that lack both function downstream of Reelin. mDab1-deficient mice VLDLR and ApoER2. Inversion of cortical layers and (identified as a naturally occurring strain called scram-absence of cerebellar foliation in these animals pre-bler and also generated by gene knockout) develop a cisely mimic the phenotype of mice lacking Reelin or phenotype indistinguishable from reeler (Sweet et al., signal to intracellular signaling processes initiated by expression is greatly increased even after the end of mDab1. the migratory period, indicating a failure of neurons to adjust its expression due to lack of Reelin signal input (Rice et al., 1998; Howell et al., 1999a). mDab1 contains Introduction a protein interaction domain that binds to NPxY motifs in the cytoplasmic tails of receptors (Pawson and Scott, The formation of the central nervous …