Editing Reelin (section)

=== During development ===
A number of non-nervous tissues and organs express reelin during development, with the expression sharply going down after organs have been formed. The role of the protein here is largely unexplored, because the knockout mice show no major pathology in these organs. Reelin's role in the growing central nervous system has been extensively characterized. It promotes the differentiation of progenitor cells into [[radial glia]] and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts.<ref name="pmid12925587" /> The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration.<ref name="pmid18197264" /> For example, reelin regulates the development of layer-specific connections in hippocampus and entorhinal cortex.<ref name="DerRio1997" /><ref name="Borrell1999" />

[[File:Reelin controls directed growth of radial fibers - journal.pone.0001454.g005 center cropped.jpg|thumb|280px|Reelin controls the direction of radial glia growth. A fragment of an [[Commons:Image:Journal.pone.0001454.g005.jpg|illustration]] from Nomura T. et al., 2008.<ref name="pmid18197264" /> Reelin-expressing cells (red) on C stimulate the growth of green glial fibers, while on B, where the red cells do not express reelin, radial glia is more disarrayed.]]

Mammalian [[corticogenesis]] is another process where reelin plays a major role. In this process the temporary layer called preplate is split into the marginal zone on the top and subplate below, and the space between them is populated by neuronal layers in the inside-out pattern. Such an arrangement, where the newly created neurons pass through the settled layers and position themselves one step above, is a distinguishing feature of mammalian brain, in contrast to the evolutionary older reptile cortex, in which layers are positioned in an "outside-in" fashion. When reelin is absent, like in the mutant [[reeler]] mouse, the order of cortical layering becomes roughly inverted, with younger neurons finding themselves to be unable to pass the settled layers. Subplate neurons fail to stop and invade the upper most layer, creating the so-called superplate in which they mix with [[Cajal-Retzius cell]]s and some cells normally destined for the second layer.{{citation needed|date=January 2016}}

[[File:An increase of Reelin-positive cells changes morphology of migrating neurons - journal.pone.0001454.g007.jpg|thumb|280px|Increased reelin expression changes the morphology of migrating neurons: unlike the round neurons with short branches (C) they assume bipolar shape (D) and attach themselves (E) to the [[radial glia]] fibers that are extending in the direction of reelin-expressing cells. Nomura T. et al., 2008.<ref name="pmid18197264" />]]

There is no agreement concerning the role of reelin in the proper positioning of cortical layers. The original hypothesis, that the protein is a stop signal for the migrating cells, is supported by its ability to induce the dissociation,<ref name="roleofreelin1" /> its role in asserting the compact granule cell layer in the hippocampus, and by the fact that migrating neuroblasts evade the reelin-rich areas. But an experiment in which murine corticogenesis went normally despite the malpositioned reelin secreting layer,<ref name="pmid16410414" /> and lack of evidence that reelin affects the growth cones and leading edges of neurons, caused some additional hypotheses to be proposed. According to one of them, reelin makes the cells more susceptible to some yet undescribed positional signaling cascade.{{citation needed|date=June 2013}}

Reelin may also ensure correct neuronal positioning in the [[spinal cord]]: according to one study, location and level of its expression affects the movement of sympathetic preganglionic neurons.<ref name="pmid19412957" />

The protein is thought to act on migrating neuronal precursors and thus 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.<ref name="roleofreelin1" /> Dissociation detaches migrating neurons from the [[glial cell]]s that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.{{citation needed|date=January 2016}}

[[File:Profile of intense and punctate reelin IR during hippocampal maturation journal pone 0005505 g001 cr.png|thumb|280px|Top: Representative image of somatic reelin immunoreactivities found in 12-day-in-vitro hippocampal neurons. Bottom: reelin immunofluorescence (red) overlaid with [[MAP2]] [[counterstain]] (green). A fragment of an [[Commons:Image:Profile of intense and punctate reelin IR during hippocampal maturation journal pone 0005505 g001.png|illustration]] from Campo et al., 2009.<ref name="pmid19430527" />]]

Reelin takes part in the developmental change of [[NMDA receptor]] configuration, increasing mobility of [[NR2B]]-containing receptors and thus decreasing the time they spend at the [[synapse]].<ref name="OlivierManzoni" />{{Dead link|date=December 2011}}<ref name="pmid15987942" /><ref name="pmid17881522" /> It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development.<ref name="pmid15470155" /> Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.<ref name="pmid19430527" />