**2. The Reelin Gene and Protein**

In humans, *RELN*, which has 94.2% homology with the mouse orthologue [8], is in chromosome 7q22 [17] and encodes for REELIN (RELN), a large glycoprotein of the extracellular matrix. The murine gene (*reln*) that also encodes for Reelin (Reln) was originally identified as the mutated gene in the *Reeler* mouse, which displays, among others, irregular lamination of the cerebral and cerebellar cortices, with an inversion of the regular 'inside-out' design observed in mammals [3,18]. The mouse and the human proteins have a similar size of 388 kDa. The structure of the protein recalls that of certain cell adhesion molecules, which specific cell types produce during brain and spinal cord development.

In the neocortex, the Cajal–Retzius cells synthesize the glycoprotein and secrete it into the extracellular space [19]. Then, in post mitotic migrating neurons, Reln activates a specific signaling pathway that is required for proper positioning of these neurons. Northern blot hybridization showed that other areas of the fetal and postnatal brain also express the protein, with levels particularly high in cerebellum.

Reln is part of a signal transduction pathway that includes the apolipoprotein E2 (ApoER2), the very low-density lipoprotein receptors (VLDLR) and the cytoplasmic protein Dab1 [20]. Notably, the brain phenotype of mice with disruptions of *mDab1* or of both *apoER2* and *vldlr* closely resemble the brain of the *Reeler* mouse [21]. Another gene that interacts with the components of the Reln signaling pathways is platelet-activating factor acetyl hydrolase IB subunit α *(PAFAH1B1)*, also referred to as *LIS1* [22].
