2ddu, 2e26, 2DDU, 2E26, 3A7Q564919699ENSG00000189056ENSMUSG00000042453P78509Q60841NM_173054NM_005045NM_011261NM_001310464NP_005036NP_774959NP_001297393NP_035391Reelin, encoded by the RELN gene,[5] is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions.

Reelin's name comes from the abnormal reeling gait of reeler mice,[17] which were later found to have a deficiency of this brain protein and were homozygous for mutation of the RELN gene.

The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developing central nervous system (CNS).

Useful spontaneous mutations were first identified by scientists who were interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage.

[citation needed] The "reeler" mouse was described for the first time in 1951 by D.S.Falconer in Edinburgh University as a spontaneous variant arising in a colony of at least mildly inbred snowy-white bellied mice stock in 1948.

[17] Histopathological studies in the 1960s revealed that the cerebellum of reeler mice is dramatically decreased in size while the normal laminar organization found in several brain regions is disrupted.

[citation needed] There followed a series of speculative reports linking reelin's genetic variation and interactions to schizophrenia, Alzheimer's disease, autism and other highly complex dysfunctions.

[50] This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, trigger Dab1 phosphorylation and mimic functions of reelin during cortical plate development.

[52] The primary functions of Reelin are the regulation of corticogenesis and neuronal cell positioning in the prenatal period, but the protein also continues to play a role in adults.

There are studies showing that along the RMS itself the two receptors, ApoER2 and VLDLR, and their intracellular adapter DAB1 function independently of Reelin,[67] most likely by the influence of a newly proposed ligand, thrombospondin-1.

[78][79][80][81] The two main reelin receptors seem to have slightly different roles: VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons.

[85] This fragment may serve postnatally to prevent apical dendrites of cortical layer II/III pyramidal neurons from overgrowth, acting via a pathway independent of canonical reelin receptors.

[91] Moreover, a Cre-loxP recombination mouse model that lacks Crk and CrkL in most neurons[92] was reported to have the reeler phenotype, indicating that Crk/CrkL lie between DAB1 and Akt in the reelin signaling chain.

[93] In addition, corticogenesis in vivo is highly dependent upon reelin being processed by embryonic neurons,[52] which are thought to secrete some as yet unidentified metalloproteinases that free the central signal-competent part of the protein.

[98] Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing the reeler phenotype, and this may indicate that a part of the signal is conducted independently of DAB1.

[51] A protein having an important role in lissencephaly and accordingly called LIS1 (PAFAH1B1), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.

Moreover, the two main receptors of reelin are able to form clusters[101] that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn.

[110] P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits,[110][111] indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.

Disruptions of the RELN gene are considered to be the cause of the rare form of lissencephaly with cerebellar hypoplasia classed as a microlissencephaly called Norman-Roberts syndrome.

The phenotype in these patients was characterized by hypotonia, ataxia, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development.

[114] Reduced expression of reelin and its mRNA levels in the brains of schizophrenia sufferers had been reported in 1998[115] and 2000,[116] and independently confirmed in postmortem studies of the hippocampus,[12] cerebellum,[117] basal ganglia,[118] and cerebral cortex.

[118] In a genetic study conducted in 2009, preliminary evidence requiring further DNA replication suggested that variation of the RELN gene (SNP rs362719) may be associated with susceptibility to bipolar disorder in women.

[164] Reelin was originally in 2001 implicated in a study finding associations between autism and a polymorphic GGC/CGG repeat preceding the 5' ATG initiator codon of the RELN gene in an Italian population.

[166] An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism.

[167] And a larger study from 2004 consisting of 395 families found no association between autistic subjects and the CGG triplet repeat as well as the allele size when compared to age of first word.

[173] According to one study, prolonged seizures in a rat model of mesial temporal lobe epilepsy have led to the loss of reelin-expressing interneurons and subsequent ectopic chain migration and aberrant integration of newborn dentate granule cells.

[189] One genome-wide association study indicates a possible role for RELN gene variation in otosclerosis, an abnormal growth of bone of the middle ear.

This suggested a potential insight into the pathophysiological involvement of reelin via inflammation and osteogenesis pathways in ankylosing spondylitis, and it could broaden the horizon toward new therapeutic strategies.

[194] According to one report, prolonged exposure to corticosterone significantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role of corticosteroids in depression.

[196] One small postmortem study has found increased methylation of RELN gene in the neocortex of persons past their puberty compared with those that had yet to enter the period of maturation.