Reelin is a protein found in the brain. It is a secreted extracellular matrix glycoprotein composed of 3461 amino acids with a relative molecular mass of 388 kDa. In the cortex and hippocampus, Reelin is secreted by Cajal-Retzius cells, Cajal cells, and Retzius cells. In the cerebellum, Reelin is expressed first in the external granule cell layer (EGL) before the granule cell migration to the internal granule cell layer (IGL)^[1].

Its name comes from the abnormal reeling gait of reeler mice^[2], which were found to have a deficiency of this brain protein and were homozygous for the reelin gene. The primary phenotype associated with loss of reeler function is inverted cortex. Inverted cortex is a neuroanatomical defect in which the six cortical layers are inverted. In humans inverted cortex is associated with severe mental retardation and epilepsy. Heterozygous mice for the reelin gene had very little obvious neuroanatomical defect but those that they had resembled the changes of the human schizophrenic brain.

During development, Reelin acts on migrating neuronal precursors and controls correct cell positioning in the cortex and other brain structures. The proposed role is one of a dissociation signal for neuronal groups, allowing them to separate and go from tangential chain-migration to radial individual migration.^[3] Dissociation displaces migrating neurons from the glial cells that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.

Reelin is cleaved in vivo at two sites located after domains 2 and 6, resulting in the production of three fragments^[4].

Reelin acts on two classes of receptors:

• VLDLR (very-low-density lipoprotein receptor) and the ApoER2 (apolipoprotein E receptor 2), which are members of the Low density lipoprotein receptor gene family.

The intracellular adaptor DAB1 binds to the VLDL receptor and ApoER2 receptor through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors.

• cadherin-related neuronal receptors(CNR).

It has been shown that alpha 3 beta 1 integrin binds to the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with other reelin receptors such as VLDLR/ApoER2.^[5]

Reelin molecules have been shown^{[6] [7]} to form a large protein complex. If the homopolymer fails to form, efficient tyrosine phosphorylation of DAB1 also fails.

The "reeler" mouse was first described in the 1951 edition of «Journal of Genetics» by Falconer D.S. ^[2] Subsequent histopathological studies revealed that the reeler cerebellum is dramatically decreased in size and the normal laminar organization found in several brain regions is disrupted (Hamburgh, 1960). In 1995, the RELN gene and protein were discovered at chromosome 7q22 by Gabriella D'Arcangelo and colleagues^[8].

Two independent mutations in the RELN gene were associated with an autosomal recessive form of lissencephaly ^[9].

Reduced expression of Reelin in schizophrenia had been reported in 1998^[10] and 2000^[11] and independently confirmed in the postmortem studies of hippocampus samples^[12] and in the cortex studies^[13][14].Hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction. ^[15] Methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mRNA levels.^{[16] [17] [18]}

A number of studies have shown an association between the reelin gene and autism^{[19] [20]}. A couple of studies were unable to duplicate linkage findings, however.^[21][22]

Decreased reelin expression in the hippocampal tissue samples from patients with temporal lobe epilepsy was found to be directly correlated to the extent of granule cell dispersion, a major feature of the disease.^{[23] [24]}

• Reelin Signaling Pathway
• The real role of reelin - publication in The Journal of Cell Biology, 2002
• Pleiotropic Action of Reelin in Psychosis - Web-lecture by Erminio Costa, MD., linking the reelin disfunction to schizophrenia and bipolar disorder.
• Gabriella D'Arcangelo - the scientist who discovered the reelin gene and protein.
• Reelin gene expression in mice - images from BGEM (Brain Gene Expression Map) site.
• Figure from an article. Corticogenesis in wild-type, reeler mutant and β1 deficient mice. - a pictorial rendition of the difference that the lack of reelin brings to the cortical structure.