Editing Reelin (section)

== Discovery ==
[[File:Reeler 100kbps.ogv|230px|thumb|left|Video: the reeler mice mutants, first described in 1951 by [[D.S.Falconer]], were later found to lack reelin protein.]]

[[File:Reeler lamination.png|thumb|250px|Normal and [[reeler]] mice brain slices.]]
Mutant mice have provided insight into the underlying molecular mechanisms of the development of the [[central nervous system]]. Useful spontaneous mutations were first identified by scientists who were interested in [[motor behavior]], and it proved relatively easy to screen [[littermate]]s for mice that showed difficulties moving around the cage. A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.{{citation needed|date=January 2016}}

The "[[reeler]]" mouse was described for the first time in 1951 by [[Douglas Scott Falconer|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.<ref name="falconer" /> [[Histopathology|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.<ref name="hamburgh" /> The 1970s brought about the discovery of cellular layer inversion in the mouse neocortex,<ref name="caviness" /> which attracted more attention to the reeler mutation.

In 1994, a new [[allele]] of reeler was obtained by means of insertional [[mutagenesis]].<ref name="pmid7972007" /> This provided the first [[molecular marker]] of the [[Locus (genetics)|locus]], permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified.<ref name="Darcan1" /> Japanese scientists at [[Kochi Medical School]] successfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specific [[monoclonal antibodies]] for reelin, and were termed CR-50 (Cajal-Retzius marker 50).<ref name="cr50" /> They noted that CR-50 reacted specifically with [[Cajal-Retzius cell|Cajal-Retzius neurons]], whose functional role was unknown until then.{{citation needed|date=January 2016}}

The Reelin receptors, [[ApoER2|apolipoprotein E receptor 2]] (ApoER2) and [[VLDLR|very-low-density lipoprotein receptor]] (VLDLR), were discovered by Trommsdorff, Herz and colleagues, who initially found that the cytosolic adaptor protein Dab1 interacts with the cytoplasmic domain of LDL receptor family members.<ref name="pmid9837937" /> They then went on to show that the double [[Gene knockout|knockout]] mice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler.<!-- this result implied that they were receptors it was the later papers that demonstrated Reelin binding that confirmed this identity.--><ref name="receptors_discovery" />

The [[Upstream and downstream (transduction)|downstream]] [[neural pathway|pathway]] of reelin was further clarified with the help of other mutant mice, including [[yotari]] and [[Scrambler mouse|scrambler]]. These mutants have phenotypes similar to that of reeler mice, but without mutation in reelin. It was then demonstrated that the mouse ''disabled homologue 1'' ([[DAB1|Dab1]]) gene is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely detectable (scrambler) in these mutants.<ref name="yotari_and_scrambler" /> Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing the [[DAB1]] as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.{{citation needed|date=January 2016}}

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. These and other discoveries, coupled with the perspective of unraveling the evolutionary changes that allowed for the creation of human brain, highly intensified the research. As of 2008, some 13 years after the gene coding the protein was discovered, hundreds of scientific articles address the multiple aspects of its structure and functioning.<ref name="reelin_G_scholar_search_title" /><ref name="Reelin_book_2008" />