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Reelin induces branching of glial cells and neurons. (A) Stripe choice assay stained for Reelin (red) and glial fibrillary acidic protein (GFAP; green). A GFAP-positive radial glial cell with its cell body located on a control stripe extends its main process to a Reelin-coated stripe (red) where it gives rise to several branches. Scale bar, 20 mm (from Förster and others 2002). (B) Cerebral cortex of a P14 Thy1–green fluorescent protein (GFP) transgenic mouse counterstained with propidium iodide (red). The apical dendrite of a layer V pyramidal cell (green), the former leading process of this neuron, branches intensely in layer I (the Reelin-containing marginal zone). Dotted lines demarcate layer I. Scale bar, 45 mm.
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Neuronal migration is an essential step of brain development and is controlled by a variety of cellular proteins and extracellular matrix molecules. Reelin, an extracellular matrix protein, is required for neuronal migration. Over the past 10 years, the Reelin signaling cascade has been studied intensively. However, the role of Reelin in neuronal m...
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... cor- tical neurons shows misoriented and less branched lead- ing processes, which do not enter the preplate (Sanada and others 2004;Kuo and others 2005). In a stripe choice assay, glial fibrillary acidic protein (GFAP)-positive radial glial cells formed many more branches on Reelin- coated stripes than on control stripes (Förster and others 2002; Fig. 1). Similarly, it has been demonstrated that Reelin induces the branching of entorhinal fibers in the dentate gyrus (Del Río and others 1997). The hypothesis that Reelin induces branching was supported by a study showing that Reelin has a serine protease activity that cleaves laminin and fibronectin in vitro, indicating that Reelin may ...
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Citations
... The reeler mouse has served the developmental neuroscience community as an insightful model system to begin understanding the seminal contributions made by reelin-secreting Cajal-Retzius cells during cortical development (Caviness et al., 1988;D'Arcangelo et al., 1997;Tissir and Goffinet, 2003;Zhao and Frotscher, 2010;Prume et al., 2018). A strong notion from early on was that the reeler cortex is inverted but preserves correct long-range wiring with different subcortical areas or nuclei (Caviness and Sidman, 1973;Caviness and Frost, 1983;Yoshihara et al., 2010;Imai et al., 2012). ...
Reelin is a large extracellular glycoprotein that is secreted by Cajal-Retzius cells during embryonic development to regulate neuronal migration and cell proliferation but it also seems to regulate ion channel distribution and synaptic vesicle release properties of excitatory neurons well into adulthood. Mouse mutants with a compromised reelin signaling cascade show a highly disorganized neocortex but the basic connectional features of the displaced excitatory principal cells seem to be relatively intact. Very little is known, however, about the intrinsic electrophysiological and morphological properties of individual cells in the reeler cortex. Repetitive burst-spiking (RB) is a unique property of large, thick-tufted pyramidal cells of wild-type layer Vb exclusively, which project to several subcortical targets. In addition, they are known to possess sparse but far-reaching intracortical recurrent collaterals. Here, we compared the electrophysiological properties and morphological features of neurons in the reeler primary somatosensory cortex with those of wild-type controls. Whereas in wild-type mice, RB pyramidal cells were only detected in layer Vb, and the vast majority of reeler RB pyramidal cells were found in the superficial third of the cortical depth. There were no obvious differences in the intrinsic electrophysiological properties and basic morphological features (such as soma size or the number of dendrites) were also well preserved. However, the spatial orientation of the entire dendritic tree was highly variable in the reeler neocortex, whereas it was completely stereotyped in wild-type mice. It seems that basic quantitative features of layer Vb-fated RB pyramidal cells are well conserved in the highly disorganized mutant neocortex, whereas qualitative morphological features vary, possibly to properly orient toward the appropriate input pathways, which are known to show an atypical oblique path through the reeler cortex. The oblique dendritic orientation thus presumably reflects a re-orientation of dendritic input domains toward spatially highly disorganized afferent projections.
... Remarkably, in the early stages of brain cortex development, the expression of the N-R6 fragment parallels the generation of L1-80. Furthermore, because newly generated neurons migrate toward the Reelin-containing marginal zone, Reelin has been considered to be a guiding signal [99]. On the other hand, Reelin might be a stop signal [99], since the migrating neurons in Reelin-deficient (reeler) mice invade the marginal zone, unlike the cells of the wild-type mice. ...
... Furthermore, because newly generated neurons migrate toward the Reelin-containing marginal zone, Reelin has been considered to be a guiding signal [99]. On the other hand, Reelin might be a stop signal [99], since the migrating neurons in Reelin-deficient (reeler) mice invade the marginal zone, unlike the cells of the wild-type mice. It is therefore worth mentioning that the developing L1-deficient cerebral cortex displays morphological abnormalities in layer formation, partially overlapping with those seen in the cerebral cortices of the reeler mice. ...
The neuronal cell adhesion and recognition molecule L1 does not only ‘keep cells together’ by way of homophilic and heterophilic interactions, but can also promote cell motility when cleaved into fragments by several proteases. It has largely been thought that such fragments are signs of degradation. Now, it is clear that proteolysis contributes to the pronounced functional diversity of L1, which we have reviewed in this work. L1 fragments generated at the plasma membrane are released into the extracellular space, whereas other membrane-bound fragments are internalised and enter the nucleus, thus conveying extracellular signals to the cell interior. Post-translational modifications on L1 determine the sequence of cleavage by proteases and the subcellular localisation of the generated fragments. Inside the neuronal cells, L1 fragments interact with various binding partners to facilitate morphogenic events, as well as regenerative processes. The stimulation of L1 proteolysis via injection of L1 peptides or proteases active on L1 or L1 mimetics is a promising tool for therapy of injured nervous systems. The collective findings gathered over the years not only shed light on the great functional diversity of L1 and its fragments, but also provide novel mechanistic insights into the adhesion molecule proteolysis that is active in the developing and diseased nervous system.
... The dentate granule neurons do not form a layered structure, but are loosely scattered in the hilus [9]. The reeler phenotype suggested that RELN acts as a positional cue during dentate gyrus development [1,10,11]. When reeler and wild-type hippocampal slices are co-cultured next to each other, the dentate granule cell layer lamination is rescued by migration of neurons and glia toward the source of RELN [12]. ...
... Reln act as both an attractive (or permissive) signal and a stop signal for cortical neurons [11,[55][56][57][58][59][60][61][62]. It is thought that APOER2 is important for the former, and VLDLR is required for the latter. ...
... It is thought that APOER2 is important for the former, and VLDLR is required for the latter. However, the granule neurons can reach the dentate gyrus without an attractive signal in reeler mice, and the role of RELN as a positional cue for hippocampal development has been more focused on the glia scaffold organization and formation of the compact granule cell layers [1,10,11]. In addition to the above model, we further propose that RELN might function as a repulsive signal locally at the fimbriodentate junction. ...
We have previously described hypomorphic reelin (Reln) mutant mice, RelnCTRdel, in which the morphology of the dentate gyrus is distinct from that seen in reeler mice. In the RelnCTRdel mutant, the infrapyramidal blade of the dentate gyrus fails to extend, while the suprapyramidal blade forms with a relatively compact granule neuron layer. Underlying this defect, we now report several developmental anomalies in the RelnCTRdel dentate gyrus. Most strikingly, the distribution of Cajal-Retzius cells was aberrant; Cajal-Retzius neurons were increased in the suprapyramidal blade, but were greatly reduced along the subpial surface of the prospective infrapyramidal blade. We also observed multiple abnormalities of the fimbriodentate junction. Firstly, progenitor cells were distributed abnormally; the "neurogenic cluster" at the fimbriodentate junction was absent, lacking the normal accumulation of Tbr2-positive intermediate progenitors. However, the number of dividing cells in the dentate gyrus was not generally decreased. Secondly, a defect of secondary glial scaffold formation, limited to the infrapyramidal blade, was observed. The densely radiating glial fibers characteristic of the normal fimbriodentate junction were absent in mutants. These fibers might be required for migration of progenitors, which may account for the failure of neurogenic cluster formation. These findings suggest the importance of the secondary scaffold and neurogenic cluster of the fimbriodentate junction in morphogenesis of the mammalian dentate gyrus. Our study provides direct genetic evidence showing that normal RELN function is required for Cajal-Retzius cell positioning in the dentate gyrus, and for formation of the fimbriodentate junction to promote infrapyramidal blade extension.
... CSF is free to diffuse across the CSF-brain interface into the ventricular zone and stimulate the stem and progenitor cells directly. Subarachnoid CSF stimulates migration and this is probably through stimulation of pial meningeal and Cajal-Retzius cells and the associated Reelin pathway involved in migration [130][131][132][133]. Unrestricted diffusion of CSF into the brain would likely produce abnormal migration with the mix of signal molecules produced. ...
The central nervous system develops around a fluid filled space which persists in the adult within the ventricles, spinal canal and around the outside of the brain and spinal cord. Ventricular fluid is known to act as a growth medium and stimulator of proliferation and differentiation to neural stem cells but the role of CSF in the subarachnoid space has not been fully investigated except for its role in the recently described "glymphatic" system. Fundamental changes occur in the control and coordination of CNS development upon completion of brain stem and spinal cord development and initiation of cortical development. These include changes in gene expression, changes in fluid and fluid source from neural tube fluid to cerebrospinal fluid (CSF), changes in fluid volume, composition and fluid flow pathway, with exit of high volume CSF into the subarachnoid space and the critical need for fluid drainage. We used a number of experimental approaches to test a predicted critical role for CSF in development of the cerebral cortex in rodents and humans. Data from fetuses affected by spina bifida and/or hydrocephalus are correlated with experimental evidence on proliferation and migration of cortical cells from the germinal epithelium in rodent neural tube defects, as well as embryonic brain slice experiments demonstrating a requirement for CSF to contact both ventricular and pial surfaces of the developing cortex for normal proliferation and migration. We discuss the possibility that complications with the fluid system are likely to underlie developmental disorders affecting the cerebral cortex as well as function and integrity of the cortex throughout life.
... The dentate granule neurons do not form a layered structure, but are loosely scattered in the hilus (Stanfield and Cowan, 1979a). The reeler phenotype suggested that RELN acts as a positional cue during dentate gyrus development Forster et al., 2006;Zhao and Frotscher, 2010). When reeler and wild-type hippocampal slices are cocultured next to each other, the dentate granule cell layer lamination is rescued by migration of neurons and glia toward the source of RELN (Zhao et al., 2004). ...
... Reln act as both an attractive (or permissive) signal and a stop signal for cortical neurons (Ogawa et al., 1995;Frotscher, 1997;Schiffmann et al., 1997;Sheppard and Pearlman, 1997;Dulabon et al., 2000;Herrick and Cooper, 2002;Olson et al., 2006;Hack et al., 2007;Zhao and Frotscher, 2010). It is thought that APOER2 is important for the former, and VLDLR is required for the latter. ...
... It is thought that APOER2 is important for the former, and VLDLR is required for the latter. However, the granule neurons can reach the dentate gyrus without an attractive signal in reeler mice, and the role of RELN as a positional cue for hippocampal development has been more focused on the glia scaffold organization and formation of the compact granule cell layers Forster et al., 2006;Zhao and Frotscher, 2010). In addition to the above model, we further propose that RELN might function as a repulsive signal locally at the fimbriodentate junction. ...
We have previously described hypomorphic reelin (Reln) mutant mice, RelnCTRdel, in which the morphology of the dentate gyrus is distinct from that seen in reeler mice. In the RelnCTRdel mutant the infrapyramidal blade of the dentate gyrus fails to extend, while the suprapyramidal blade forms with a relatively compact granule neuron layer. The distribution of Cajal-Retzius cells in the dentate gyrus was aberrant; Cajal-Retzius neurons were increased in the suprapyramidal blade, but were greatly reduced along the subpial surface of the prospective infrapyramidal blade. We also observed multiple abnormalities of the fimbriodentate junction. Firstly, progenitor cells were distributed abnormally; the neurogenic cluster at the fimbriodentate junction was absent, lacking the normal accumulation of Tbr2-positive intermediate progenitors. However, the number of dividing cells in the dentate gyrus was not generally decreased. Secondly, a defect of secondary glial scaffold formation, limited to the infrapyramidal blade, was observed. The densely radiating glial fibers characteristic of the normal fimbriodentate junction were absent in mutants. These fibers might be required for migration of progenitors, which may account for the failure of neurogenic cluster formation. These findings suggest the importance of the secondary scaffold and neurogenic cluster of the fimbriodentate junction in morphogenesis of the mammalian dentate gyrus. Our study provides direct genetic evidence showing that normal RELN function is required for Cajal-Retzius cell positioning in the dentate gyrus, and for formation of the fimbriodentate junction to promote infrapyramidal blade extension.
... Reelin (RL) is a chemotactic glycoprotein from the extracellular matrix that is widely produced during neurodevelopment and participates in neuronal migration [299]. In the adult brain, RL plays a role in the memory and synaptic plasticity by modulation of NMDA receptor activity, enhancement of LTP [300], and stabilization of the cytoskeleton actin [301]. ...
Alzheimer's disease (AD) is a neurodegenerative disorder that drastically compromises patients' and relatives' quality of life, besides being a significant economic burden to global public health. Its pathophysiology is not completely elucidated yet, hence, the current therapies are restricted to treating the symptoms. Over the years, several epidemiological studies have shown disproportionalities in AD when sex is considered, which has encouraged researchers to investigate the potentiality of sex as a risk factor. Studies in rodent models have been used to investigate mechanistic basis of sex differences in AD, as well as the development of possible new sex-specific therapeutic strategies. However, full knowledge on factors related to this sexual dimorphism remains to be unraveled. Some findings point to differences in genetic and developmental backgrounds either earlier in life or in the aging brain. Herein we summarize the multisystemic framework behind the sex differences in AD and discuss the possible mechanisms involved in these differences raised by the literature so far in an integrative perspective.
... The Reelin-Dab1 signaling cascade is the best-studied signaling pathway regulating neuronal migration and cortical lamination (Franco et al., 2011;Simó and Cooper, 2013;Zhao and Frotscher, 2010). Dab1, the key adaptor protein in this pathway, binds to the transmembrane receptors apolipoprotein e receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR) and subsequently activates downstream effectors (D'Arcangelo et al., 1999;Hiesberger et al., 1999;Trommsdorff et al., 1999). ...
Newborn neurons undergo inside-out migration to their final destinations during neocortical development. Reelin-induced tyrosine phosphorylation of disabled 1 (Dab1) is a critical mechanism controlling cortical neuron migration. However, the roles of Reelin-independent phosphorylation of Dab1 remain unclear. Here, we report that deleted in colorectal carcinoma (DCC) interacts with Dab1 via its P3 domain. Netrin 1, a DCC ligand, induces Dab1 phosphorylation at Y220 and Y232. Interestingly, knockdown of DCC or truncation of its P3 domain dramatically delays neuronal migration and impairs the multipolar-to-bipolar transition of migrating neurons. Notably, the migration delay and morphological transition defects are rescued by the expression of a phospho-mimetic Dab1 or a constitutively active form of Fyn proto-oncogene (Fyn), a member of the Src-family tyrosine kinases that effectively induces Dab1 phosphorylation. Collectively, these findings illustrate a DCC-Dab1 interaction that ensures proper neuronal migration during neocortical development.
... During cortical cell layer formation, Reelin has been reported, for instance, to act as a chemoattractant to migrating Purkinje cells and pre-migratory cortical neurons of the ventricular zone (Gilmore and Herrup, 2000;Magdaleno et al., 2002;Miyata et al., 1997), a repellent cue to subplate neurons (Ogawa et al., 1995), or as detachment/stop signal from radial glia for neurons during the terminal phase of migration (Dulabon et al., 2000;Hack et al., 2002;Sanada et al., 2004). It has therefore been suggested that Reelin signaling can have multiple roles during different phases of neuronal migration being attractive/growth promoting during the initial stages and a detachment/stop signal during later stages of the migration process (Feng and Cooper, 2009;Zhao and Frotscher, 2010). We demonstrated here that the Reelin gradient has an attractive effect on RGC axons, indicative of a mechanism in which RGCs expressing high levels of functional VLDLR project to superficial laminae with high Reelin concentrations, whereas RGCs expressing low functional VLDLR project to deep laminae with low Reelin concentrations. ...
A conserved organizational and functional principle of neural networks is the segregation of axon-dendritic synaptic connections into laminae. Here we report that targeting of synaptic laminae by retinal ganglion cell (RGC) arbors in the vertebrate visual system is regulated by a signaling system relying on target-derived Reelin and VLDLR/Dab1a on the projecting neurons. Furthermore, we find that Reelin is distributed as a gradient on the target tissue and stabilized by heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM). Through genetic manipulations, we show that this Reelin gradient is important for laminar targeting and that it is attractive for RGC axons. Finally, we suggest a comprehensive model of synaptic lamina formation in which attractive Reelin counter-balances repulsive Slit1, thereby guiding RGC axons toward single synaptic laminae. We establish a mechanism that may represent a general principle for neural network assembly in vertebrate species and across different brain areas.
... We next investigated a possible mechanism underlying abnormal migration of neurons into LGH. It was previously reported that reelin-expressing Cajal-Retzius (CR) cells were reduced in mice exhibiting LGH (1,29), and that the depletion of reelin resulted in over-migration of cortical neurons into the marginal zone of the mouse cerebral cortex (30). We therefore hypothesized that reelin expression was affected in TD ferrets. ...
Leptomeningeal glioneuronal heterotopia (LGH) is a focal malformation of the cerebral cortex and frequently found in patients with thanatophoric dysplasia (TD). The pathophysiological mechanisms underlying LGH formation are still largely unclear because of difficulties in obtaining brain samples from human TD patients. Recently, we established a new animal model for analyzing cortical malformations of human TD by utilizing our genetic manipulation technique for gyrencephalic carnivore ferrets. Here we investigated the pathophysiological mechanisms underlying the formation of LGH using our TD ferrets. We found that LGH was formed during corticogenesis in TD ferrets. Interestingly, we rarely found Ki-67-positive and phospho-histone H3-positive cells in LGH, suggesting that LGH formation does not involve cell proliferation. We uncovered that vimentin-positive radial glial fibers and doublecortin-positive migrating neurons were accumulated in LGH. This result may indicate that preferential cell migration into LGH underlies LGH formation. Our findings provide novel mechanistic insights into the pathogenesis of LGH in TD.
... Moreover, a role for Reelin in the directed migration of cortical neurons is consistent with the observation that in reeler late-generated neurons are unable to migrate through deep, early-generated cell layers, likely because their attractive force is missing in the mutant (Zhao et al., 2004). However, in reeler, but not in wild type, layer I of the cortex, the former MZ, is densely populated, suggesting an opposite effect, a stop signal function for Reelin (Zhao and Frotscher, 2010). Could it be that full-length Reelin in the MZ has different functions than the various Reelin fragments, diffusing to deeper cortical layers? ...
... In the present review article we will not discuss other molecules of the Reelin signaling cascade in detail but will focus on Reelin's role in the stabilization of the actin cytoskeleton as an important prerequisite for the stability of the leading process which is needed for nuclear translocation during migratory activity. The reader is referred to several other review articles dealing in more detail with the various aspects of Reelin function (Rakic and Caviness, 1995;Curran and D'Arcangelo, 1998;Frotscher, 1998Frotscher, , 2010Jossin et al., 2003;Tissir and Goffinet, 2003;Förster et al., 2006a,b;Cooper, 2008Cooper, , 2013Zhao and Frotscher, 2010;Chai and Frotscher, 2016). ...
Neurons are highly polarized cells. They give rise to several dendrites but only one axon. In addition, many neurons show a preferred orientation. For example, pyramidal neurons of the cerebral cortex extend their apical dendrites toward the cortical surface while their axons run in opposite direction toward the white matter. This characteristic orientation reflects the migratory trajectory of a pyramidal cell during cortical development: the leading process (the future apical dendrite) extends toward the marginal zone (MZ) and the trailing process (the future axon) toward the intermediate zone (IZ) while the cells migrate radially to reach their destination in the cortical plate (CP). In this review article, we summarize the function of Reelin, an extracellular matrix protein synthesized by Cajal-Retzius cells in the MZ, in the development of the characteristic orientation of the leading processes running perpendicular to the cortical surface. Reelin promotes migration toward the cortical surface since late-generated cortical neurons in the reeler mutant are unable to reach upper cortical layers. Likewise, Reelin is important for the orientation and maintenance of the leading processes of migrating neurons since they are misoriented in the developing reeler cortex, as are the apical dendrites of pyramidal cells in the mature mutant. Reelin-induced phosphorylation of cofilin, an actin-associated protein, is crucial since pyramidal neurons transfected by in utero electroporation (IUE) with a non-phosphorylatable form of cofilin (cofilinS3A) show severe migration defects reminiscent of those in the reeler mutant. Remarkably, migration of neurons in the cortex of reeler mice was partially rescued by transfecting them with LIM kinase 1 (LIMK1), the kinase that induces phosphorylation of cofilin at serine3, or with a pseudo-phosphorylated cofilin mutant (cofilinS3E). Together these results indicate that Reelin-induced phosphorylation of cofilin is an important component in the orientation and directed migration of cortical neurons and in their correct lamination.
