Editing Reelin (section)

==Mechanism of action==
[[File:Model of Reelin and Lis1 signaling - journal.pone.0000252.g008.png|thumb|280px|The main reelin signaling cascade (ApoER2 and VLDLR) and its interaction with [[LIS1]]. Zhang et al., 2008<ref name="Zhang_2007_Pafah1b" /><br /> '''SFK''': [[Src Family Kinases|Src family kinases]].<br />'''JIP''': [[MAPK8IP1|JNK-interacting protein 1]]]]

=== Receptors ===
Reelin's control of cell-cell interactions is thought to be mediated by binding of reelin to the two members of [[low density lipoprotein receptor gene family]]: [[VLDL receptor|VLDLR]] and the [[low density lipoprotein receptor-related protein 8|ApoER2]].<ref name="pmid10571240" /><ref name="pmid10571241" /><ref name="pmid12899622" /><ref name="pmid12670700" /> 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.<ref name="pmid17913789" /> It also has been shown that the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with VLDLR/ApoER2 binds to the alpha-3-beta-1 [[integrin]] receptor.<ref name="integrin" /> The proposal that the proto[[cadherin]] CNR1 behaves as a Reelin receptor<ref name="cadherin" /> has been disproven.<ref name="centralfragment" />

As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain called [[NPxY]] [[Structural motif|motif]]. After binding to the receptors reelin is internalized by [[endocytosis]], and the N-terminal fragment of the protein is re-secreted.<ref name="pmid19303411" /> 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.<ref name="pmid19366679" />

Reelin receptors are present on both [[neuron]]s and [[glial cell]]s. Furthermore, [[radial glia]] express the same amount of [[Low density lipoprotein receptor-related protein 8|ApoER2]] but being ten times less rich in [[VLDL receptor|VLDLR]].<ref name="pmid12925587" /> [[CD29|beta-1 integrin receptors]] on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.<ref name="pmid18077697" />

Reelin-dependent strengthening of [[long-term potentiation]] is caused by [[ApoER2]] interaction with [[NMDA receptor]]. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity.<ref name="Reelin_ApoER2_Exon19_2005_Beffert" /> According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as [[demethylase]]s open up the RELN gene.<ref name="pmid17359920" /> The activation of dendrite growth by reelin is apparently conducted through [[Src (gene)|Src]] family [[kinase]]s and is dependent upon the expression of [[CRK (gene)|Crk]] family proteins,<ref name="pmid18477607" /> consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1.<ref name="pmid15062102" /> Moreover, a [[Cre-Lox recombination|Cre-loxP recombination]] mouse model that lacks [[CRK (gene)|Crk]] and [[CRKL|CrkL]] in most neurons<ref name="pmid19074029" /> was reported to have the [[reeler]] phenotype, indicating that Crk/CrkL lie between [[DAB1]] and [[AKT1|Akt]] in the reelin signaling chain.

=== Signaling cascades ===
Reelin activates the signaling cascade of [[NOTCH1|Notch-1]], inducing the expression of [[FABP7]] and prompting progenitor cells to assume [[radial glia]]l phenotype.<ref name="pmid18593473" /> In addition, corticogenesis ''in vivo'' is highly dependent upon reelin being processed by embryonic neurons,<ref name="pmid17442808" /> which are thought to secrete some as yet unidentified [[metalloproteinase]]s that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role.<ref name="pmid12959647" /> It is supposed that full-sized reelin sticks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of reelin, are able to permeate into the lower levels.<ref name="pmid17442808" /> It is possible that as [[neuroblast]]s reach the higher levels they stop their migration either because of the heightened combined expression of all forms of reelin, or due to the peculiar mode of action of the full-sized reelin molecules and its homodimers.<ref name="Reelin_book_2008" />

The intracellular adaptor [[DAB1]] binds to the VLDLR and ApoER2 through an [[NPxY]] motif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated by [[Src (gene)|Src]]<ref name="pmid9009273" /> and [[FYN|Fyn]]<ref name="pmid12526739" /> kinases and apparently stimulates the [[actin]] cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in [[Cell adhesion|adhesion]]. Phosphorylation of DAB1 leads to its [[ubiquitination]] and subsequent degradation, and this explains the heightened levels of DAB1 in the absence of reelin.<ref name="pmid17974915" /> Such [[negative feedback]] is thought to be important for proper cortical lamination.<ref name="pmid18006681" /> 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.<ref name="centralfragment" />

[[File:Reelin induces GFAP and FABP7 via Notch1.jpg|thumb|280px|Reelin stimulates the progenitor cells to differentiate into radial glia, inducing the expression of radial glial marker [[FABP7|BLBP]] by affecting the [[NOTCH1]] cascade. A fragment of an [[Commons:Image:Reelin-induced radial glial phenotype is dependent on gamma-secretase activity.jpg|illustration]] from Keilani et al., 2008.<ref name="pmid18593473" />]]

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.<ref name="Zhang_2007_Pafah1b" />

=== Complexes ===
Reelin molecules have been shown<ref name="hugecomplex" /><ref name="complex" /> to form a large protein complex, a [[disulfide bond|disulfide-linked]] [[homodimer]]. If the homodimer fails to form, efficient tyrosine [[phosphorylation]] of DAB1 ''in vitro'' fails. Moreover, the two main receptors of reelin are able to form clusters<ref name="pmid14729980" /> that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn. Such clustering has been shown in the study to activate the signaling chain even in the absence of Reelin itself.<ref name="pmid14729980" /> In addition, reelin itself can cut the peptide bonds holding other proteins together, being a [[serine protease]],<ref name="pmid11689558" /> and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation of [[actin]]-interacting protein [[cofilin 1]] at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.<ref name="pmid19129405" /><ref name="pmid19396394" />

=== Interaction with Cdk5 ===
[[Cyclin-dependent kinase 5]] (Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate [[DAB1]]<ref name="pmid14645539" /><ref name="pmid16529723" /><ref name="pmid12077184" /> and other cytosolic targets of reelin signaling, such as [[Tau protein|Tau]],<ref name="pmid8253190" /> which could be activated also via reelin-induced deactivation of [[GSK3B]],<ref name="pmid12376533" /> and [[NDEL1|NUDEL]],<ref name="pmid11163259" /> associated with [[PAFAH1B1|Lis1]], one of the DAB1 targets. [[Long-term potentiation|LTP]] induction by reelin in hippocampal slices fails in [[CDK5R1|p35]] knockouts.<ref name="pmid14985430" /> P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits,<ref name="pmid14985430" /><ref name="pmid11226314" /> indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.