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PubMed1999

Transient and compartmental expression of the reeler gene product reelin in the developing rat striatum.

Mammalian neostriatum is composed of two neurochemically and neuroanatomically defined compartments, called the patches and matrix. The present study concerns a search for neurochemical molecules involved in formation of the striatal compartments. Using the monoclonal antibody CR-50, we here disclose a transient expression of the reeler gene product Reelin, which is known to play a crucial role in neuronal positioning and axon guidance during corticogenesis, in the developing striatum of rats. Furthermore, Reelin protein is differentially concentrated in the two distinct compartments showing a mosaic-like fashion in the early postnatal period: the compartments of heightened CR-50-immunolabeling correspond to so-called "dopamine islands" (i.e., developing striosomes) visualized by tyrosine hydroxylase (TH)-immunostaining. On the basis of these findings, we hypothesize that Reelin protein may play a role in developmental organization of the striatal compartments.

Animals↗
PubMed2005

Apoer2: a reelin receptor to remember.

The extracellular protein Reelin is crucial for neuronal positioning during brain development, but its expression persists long after cell migration is completed. In this issue of Neuron, Beffert et al. demonstrate that Reelin exerts an additional function in the mature brain, to modulate synaptic plasticity and to favor memory formation. This activity is carried out exquisitely by the Apoer2 receptor and critically requires the presence of an alternatively spliced exon. This exon encodes an intracellular domain that interacts with postsynaptic proteins and promotes binding and phosphorylation of NMDA receptors.

Alternative Splicing↗
PubMed2000

The Reelin signaling pathway in mouse cortical development.

Most of the cerebral cortex derives from the cortical plate which, in all mammals, is radially organized and develops from inside to outside. Several genes involved in the organization and inside-outside development of the embryonic cortical plate in the mouse form the so-called Reelin signaling pathway. Biochemical and genetic arguments show that the extracellular matrix protein Reelin binds to two lipoprotein receptors (VLDLR and ApoER2), which relay the Reelin signal inside target neurons by docking the tyrosine kinase adapter disabled-1 (Dab1). In addition, biochemical evidence suggests that the integrins alpha 3/beta 1 and protocadherins of the CNR family may also modulate the Reelin signal. The mechanisms by which the presence of Reelin stops migration and instructs the radial organization of cortical plate cells remains unknown.

Animals↗
PubMedDate not supplied

An hypothesis on the early evolution of the development of the isocortex.

We propose an hypothesis on the evolutionary origin of the unique inside-out developmental gradient of the isocortex, in which deep layers originate before superficial layers. This contrasts with the development of the reptilian cortex, which originates in an outside-in gradient. In mice, a mutated protein, reelin, produces the reeler phenotype, whose cortex has an outside-in neurogenetic gradient like in reptiles. Reelin is normally located in the marginal layer of the developing cerebral cortex, and its normal function has been proposed to be a stop signal that prevents radially migrating cells from moving into the marginal zone. Additionally, mutations on the kinase Cdk5, or in its neuronal-specific activator p35, produce a deficit similar to reeler in that the neurogenetic gradient is outside-in. However, contrary to reeler, in which no cell-sparse layer I is observed, in these mice, a well-defined layer I exists, which suggests that migrating cells respond normally to reelin. Apparently, Cdk5/p35 participate in permitting cortical cells to move across pre-existing (earlier produced) cortical layers, in order to be able to contact reelin once they reach the marginal zone. We suggest that the evolutionary advent of the mammalian cortical inside-out gradient became partly possible through the activation of the Cdk5/p35 pathway, which permitted migrating cells to move across layers of older cells. At about the same time, reelin became an important element in cortical development as it prevented neuronal migration into the marginal zone (cortical layer I) and facilitated the migration of neurons past postmigratory elements.

Animals↗
PubMed2006

Paradoxical effects of prenatal acetylcholinesterase blockade on neuro-behavioral development and drug-induced stereotypies in reeler mutant mice.

INTRODUCTION: Epidemiological and experimental studies support a link between genetic and epigenetic factors in vulnerability to develop enduring neurobehavioral alterations. We studied the interplay between genetic vulnerability and the prenatal exposure to a neurotoxic compound. Chlorpyrifos, a potent and reversible acetylcholinesterase blocker used as a pesticide, and the "reeler" mouse, lacking the extracellular-matrix protein Reelin, were used. MATERIALS AND METHODS: Homozygous reeler (RL), heterozygous (HZ), and wild-type (WT) mice were prenatally exposed to chlorpyrifos-oxon (CPF-O), the active metabolite of chlorpyrifos, or to vehicle (prenatal controls) on gestation days 14-16, that is, during a peak period of neurogenesis in the cerebral cortex. The offspring was reared by the natural dam and tested during infancy and at adulthood for global consequences of the prenatal exposure. CONCLUSION: The results are consistent with complex interactions between genetic (reeler genotype) and epigenetic (prenatal exposure to CPF-O) factors. In the case of some "genetically modulated" parameters (ultrasound vocalization, amphetamine-induced locomotion, and stereotypy), exposure to CPF-O paradoxically reverted the effects produced by progressive reelin absence. Conversely, for an "epigenetically modulated" parameter (grasping reflex maturation), the effects of CPF-O exposure were counteracted by progressive reelin absence. Finally, for parameters apparently untouched by either factor alone (righting reflex latency, scopolamine-induced locomotor activity), prenatal CPF-O exposure unmasked an otherwise latent genotype dependency. This complex picture also points to reciprocal adaptations within cholinergic and dopaminergic systems during development. Data are interesting in view of recently discovered cholinergic abnormalities in autism and schizophrenia, and may suggest new avenues for early intervention.

Amphetamine↗
PubMed2005

Expression of reelin in the dorsal cochlear nucleus of the mouse.

The cytoarchitecture of dorsal cochlear nucleus (DCN), characterized by a distinct laminar structure similar to the cerebellar cortex of the normal mouse, is known to be disrupted in the Reelin-deficient mouse, reeler. Here, we have reexamined both the cytoarchitecture and myeloarchitecture of this nucleus and described expression pattern of Reelin protein during perinatal periods. Reelin-immunopositive granule cells were firstly recognized in the external granular layer of the DCN at embryological day 16 (E16). Next, we examined the cytoarchitecture of the DCN of the normal and reeler mice with Ca2+/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) immunostaining. CaMKIIalpha-immunoreactive cartwheel cells were laminarly distributed in the layer II of the normal DCN, but scattered throughout the reeler DCN. Injection of retrograde tracer, Fluoro-Gold (FG) into the inferior colliculus of the reeler mouse resulted in that retrogradely labeled neurons in the DCN were radially scattered instead of being confined to a single layer as seen in the normal mouse. To examine whether CaMKIIalpha-immunopositive cartwheel cells are neurons projecting to the inferior colliculus or not, double labeling with CaMKIIalpha immunohistochemistry and retrograde labeling with an injection of FG into the inferior colliculus were made, which revealed that CaMKIIalpha-immunoreactive cartwheel cells do not send axons to the inferior colliculus. The present findings imply that Reelin may have some roles in the formation of laminar structures of the DCN.

Animals↗
PubMed2002

Conserved and divergent patterns of Reelin expression in the zebrafish central nervous system.

The protein Reelin is suggested to function in cell-cell interactions and in mediating neuronal migrations in layered central nervous system structures. With the aim of shedding light on the development of the teleost telencephalon, which forms through the process of eversion and results in the formation of a nonlaminar pallium, we isolated a zebrafish ortholog of the reelin gene and studied its expression in developing and adult brain. The pattern of expression is highly dynamic during the first 24-72 hours of development. By 5 days postfertilization, high amounts of reelin mRNA are found in the dorsal telencephalon, thalamic and hypothalamic regions, pretectal nuclei, optic tectum, cerebellum, hindbrain, reticular formation, and spinal cord, primarily confined to postmitotic neurons. This pattern persists in 1- to 3-month-old zebrafish. This study, together with reports on reelin expression in other vertebrates, shows that reelin mRNA distribution is conserved in many regions of the vertebrate brain. A major exception is that reelin is expressed in the majority of the cells of the dorsal regions of the everted telencephalon in zebrafish embryos, whereas it is restricted to specific neuronal populations in the developing telencephalon of amniotes. To better understand the origin of these differences, we analyzed reelin expression in the telencephalon of an amphibian. Telencephalic reelin expression in Xenopus laevis shows more similarities with the sauropsidian than with the teleostean pattern. Thus, the differences in the telencephalic expression of reelin between teleosts and tetrapods are likely to be due to different roles for Reelin during eversion, a process that is specific for the teleost telencephalon.

Aging↗
PubMed2006

A mouse homologue of Strawberry Notch is transcriptionally regulated by Reelin signal.

Reelin is a glycoprotein secreted by specific neuronal populations of the adult and developing nervous system of vertebrates. The morphological abnormalities in the brain of reeler, the Reelin deficient mutant mice, indicate that Reelin is essential for the brain morphogenesis. However, biochemical function of Reelin signal is not well understood. Here, we examined possible function of Reelin signal in regulation of gene expression by performing a microarray analysis. We found that expression level of a mouse homologue of Strawberry Notch (mSno1) is markedly reduced in the reeler embryos. In situ hybridization showed that mSno1 is expressed in the developing nervous system colocalizing with expression of ApoER2, a Reelin receptor. Treatment of P19 cells with Reelin protein enhanced mSno1 expression. Overexpression of ApoER2 with Reelin treatment gave a synergistic effect on mSno1 expression level. These observations suggest that Reelin signal is involved in embryonic expression of a novel vertebrate gene, mSno1.

Animals↗
PubMed1999

Reelin is a ligand for lipoprotein receptors.

A signaling pathway involving the extracellular protein Reelin and the intracellular adaptor protein Disabled-1 (Dab1) controls cell positioning during mammalian brain development. Here, we demonstrate that Reelin binds directly to lipoprotein receptors, preferably the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Binding requires calcium, and it is inhibited in the presence of apoE. Furthermore, the CR-50 monoclonal antibody, which inhibits Reelin function, blocks the association of Reelin with VLDLR. After binding to VLDLR on the cell surface, Reelin is internalized into vesicles. In dissociated neurons, apoE reduces the level of Reelin-induced tyrosine phosphorylation of Dab1. These data suggest that Reelin directs neuronal migration by binding to VLDLR and ApoER2.

Animals↗
PubMed2003

Malformation of the radial glial scaffold in the dentate gyrus of reeler mice, scrambler mice, and ApoER2/VLDLR-deficient mice.

We studied the postnatal development of the radial glial scaffold in the dentate gyrus of reeler mice, lacking the extracellular matrix protein Reelin, in scrambler mice, deficient in the intracellular adaptor protein disabled1 (Dab1), which is required for the transmission of the Reelin signal into the cell, and in mutant mice lacking the Reelin receptors apolipoprotein receptor 2 (ApoER2) and/or the very low density lipoprotein receptor (VLDLR), known to transmit the Reelin signal via Dab1. By immunolabeling for the glial fibrillary acidic protein (GFAP), we show that a regular dentate radial glial scaffold fails to form in mutants deficient of Reelin, Dab1, and VLDLR and ApoER2. Mutant mice lacking only one of the Reelin receptors, VLDLR or ApoER2, display a gradual expression of the radial glial defects seen in mutants that lack both receptors. Our results suggest that Reelin signaling via ApoER2, VLDLR, and Dab1 is required for the formation of a regular radial glial scaffold in the dentate gyrus.

Animals↗
PubMed2006

Reelin expression and glycosylation patterns are altered in Alzheimer's disease.

Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the developing CNS. Its function in the adult brain is less understood, although it has been proposed that Reelin is involved in signaling pathways linked to neurodegeneration. Here we analyzed Reelin expression in brains and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and nondemented controls. We found a 40% increase in the Reelin protein levels in the cortex of AD patients compared with controls. Similar increases were detected at the Reelin mRNA transcriptional level. This expression correlates with parallel increases in CSF but not in plasma samples. Next, we examined whether CSF Reelin levels were also altered in neurological diseases, including frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease. The Reelin 180-kDa band increased in all of the neurodegenerative disorders analyzed. Moreover, the 180-kDa Reelin levels correlated positively with Tau protein in CSF. Finally, we studied the pattern of Reelin glycosylation by using several lectins and the anti-HNK-1 antibody. Glycosylation differed in plasma and CSF. Furthermore, the pattern of Reelin lectin binding differed between the CSF of controls and in AD. Our results show that Reelin is up-regulated in the brain and CSF in several neurodegenerative diseases and that CSF and plasma Reelin have distinct cellular origins, thereby supporting that Reelin is involved in the pathogenesis of a number of neurodegenerative diseases.

Alzheimer Disease↗
PubMed2001

The inverted neurogenetic gradient of the mammalian isocortex: development and evolution.

In this paper we review recent evidence on the molecular control of cell migration in the isocortex, and present an hypothesis for the evolutionary origin of the inside-out neurogenetic gradient of this structure. We suggest that there are at least two key factors involved in the acquisition of the inside-out gradient: (i) the expression of the protein reelin, which arrests the migration of cortical plate cells by detaching them from the radial glial fiber. This permits younger neurons to use the same fiber to migrate past the previous neurons; and (ii) the second factor is an intracellular signaling pathway dependent on a cyclin-dependent protein kinase (Cdk5). Cdk5 may work by inhibiting N-cadherin mediated cell aggregation as young cells cross the cortical plate, permitting them to move to the more superficial layers. Interestingly, the mutation in Cdk5 affects the migration of only those cells belonging to superficial layers, which are considered to be an evolutionary acquisition of the mammalian isocortex.

Animals↗
PubMed1998

Cerebellar abnormalities in the disabled (mdab1-1) mouse.

A mouse homolog of the Drosophila Disabled (dab) gene, disabled-1 (mdab1), encodes an adaptor molecule that functions in neural development. Targeted disruption of the mdab1 gene (mdab1-1 mice) leads to anomalies in the development of the cerebrum, hippocampus, and cerebellum. Here we describe a number of histologic abnormalities in the cerebellum of the mdab1-1 mouse. There is a complete absence of foliation, and most Purkinje cells are clumped in central clusters. However, lamination appears to develop normally in areas where the Purkinje cells and external granular layer are closely apposed. The granular layer forms a thin rind over most of the cerebellar surface, but is subdivided by both transverse and parasagittal boundaries. The Purkinje cells, identified by anti-zebrin II in the adult or anti-calbindin in the new born mdab1-1 mutant cerebellum, form a parasagittal banding pattern, similar to but distorted compared with the wild-type design. The data suggest that the development of the mdab1-1 cerebellum parallels the development of reeler. The reeler gene encodes an extracellular protein (Reelin) that is secreted by the external granular layer. Because Reelin expression is retained in the mdab1-1 mutant mouse, mDab1 p80 may act in a parallel pathway or downstream of Reelin, leading to the transformation of embryonic Purkinje cell clusters into the adult parasagittal bands.

Animals↗
PubMed2003

Cytoarchitecture and fiber pattern of the superior colliculus are disrupted in the Shaking Rat Kawasaki.

Shaking Rat Kawasaki (SRK) is a Reelin-deficient rat, that shows significant cytoarchitectural abnormalities in the cerebral and cerebellar cortices in a similar manner to the reeler malformation. In the present study, we investigated the cytoarchitecture and myeloarchitecture of the superior colliculus (SC) of this mutant rat. The Nissl staining clearly showed that neuronal components in the superficial layers of the SC in SRK rat were intermingled with each other and that the boundaries between these superficial layers were blurred. The MBP immunohistochemistry showed an abnormal fiber pattern in the superficial layers of the SC of this mutant rat. In the normal rat, myelinated fibers passed rostrocaudally through the optic layer, and only a few myelinated fibers were recognized in the uppermost two layers, i.e., the zonal and superficial gray layers. By contrast, in SRK rat, the myelinated fibers were distributed throughout the entire thickness of the superficial layers of the SC. Anterograde labeling of retinotectal fibers with an injection of Cholera Toxin subunit B into the retina revealed that this abnormal fiber pattern was associated with the anomalous course of the retinotectal fibers. No distinct differences in the cytoarchitecture and fiber pattern in the deep layers of the SC were seen. In conclusion, the present study demonstrated that the cytoarchitecture and fiber patterning in the superficial layers of the SC were disrupted in SRK rat, suggesting that Reelin protein regulates the formation of the superficial layers of the SC.

Animals↗
PubMed1999

Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.

The large extracellular matrix protein Reelin is produced by Cajal-Retzius neurons in specific regions of the developing brain, where it controls neuronal migration and positioning. Genetic evidence suggests that interpretation of the Reelin signal by migrating neurons involves two neuronal cell surface proteins, the very low density lipoprotein receptor (VLDLR) and the apoE receptor 2 (ApoER2) as well as a cytosolic adaptor protein, Disabled-1 (Dab1). We show that Reelin binds directly and specifically to the ectodomains of VLDLR and ApoER2 in vitro and that blockade of VLDLR and ApoER2 correlates with loss of Reelin-induced tyrosine phosphorylation of Disabled-1 in cultured primary embryonic neurons. Furthermore, mice that lack either Reelin or both VLDLR and ApoER2 exhibit hyperphosphorylation of the microtubule-stabilizing protein tau. Taken together, these findings suggest that Reelin acts via VLDLR and ApoER2 to regulate Disabled-1 tyrosine phosphorylation and microtubule function in neurons.

Animals↗
PubMed2004

High affinity binding of Dab1 to Reelin receptors promotes normal positioning of upper layer cortical plate neurons.

The positions of neurons in the neocortex, hippocampus, cerebellum and various other laminated brain regions are regulated by a signaling pathway initiated by the secreted protein Reelin and requiring the intracellular adaptor protein Dab1. Dab1 and the Reelin receptors VLDLR and ApoER2 are expressed by neurons whose migrations are coordinated by Reelin. In vitro, Dab1 binds with high affinity to the cytoplasmic tails of VLDLR and ApoER2 via its PTB domain. To test the importance of Dab1 binding to VLDLR and ApoER2, we replaced the Dab1 gene with a cDNA cassette encoding a point mutant allele, Dab1(F158V). This mutation strongly decreases Dab1 binding in vitro to peptides containing the ApoER2 or VLDLR cytoplasmic regions. Surprisingly, Dab1(F158V/F158V) homozygotes have no discernable phenotype. However, Dab1(F158V/-) hemizygous animals have a subtle phenotype in which late-generated cortical plate neurons migrate excessively into the marginal zone. Early cortical plate neurons, subplate neurons, hippocampal pyramidal cells and cerebellar Purkinje cells are positioned normally. Thus Dab(F158V) is a weak loss-of-function (hypomorphic) allele that has no detectable effect when homozygous. The phenotype of Dab1(F158V/-) hemizygotes shows that late cortical plate neurons of layers 2-3 require efficient Reelin-Dab1 signaling to prevent them entering the marginal zone. The Dab1(F158V) allele adds to a series of Dab1 alleles that demonstrates cell type-specific variation in the Reelin-Dab1 pathway.

Age Factors↗
PubMed2006

Comparative aspects of p73 and Reelin expression in Cajal-Retzius cells and the cortical hem in lizard, mouse and human.

Cajal-Retzius (CR) cells of the mammalian neocortex co-express the extracellular matrix protein Reelin and p73, a transcription factor involved in cell death and survival. Most neocortical CR cells derive from the cortical hem, with minor additional sources. We analyzed the distribution of Reelin and p73 immunoreactive (ir) neurons in the telencephalon of Lacerta galloti from early embryonic stages to hatching. Numerous Reelin-ir cells appeared in the pallial MZ from the preplate stage onward. Conversely, p73-ir cells were rare in the pallial preplate and not observed in the cortical plate. Subpallial p73-ir cells spread from the septum and the telencephalic-diencephalic boundary to the pial surface of the basal forebrain and amygdala, respectively, where they co-expressed Reelin and p73. A small group of Reelin/p73-ir CR cells appeared in a rudimentary cortical hem at the interface of the medial cortex and choroid plexus. Comparison with early embryonic stages of mice and humans showed similar foci of p73-ir cells in the septum and at the telencephalic-diencephalic boundary and revealed an increasing prominence of the cortical hem, in parallel with increasing numbers of neocortical Reelin/p73 positive CR cells, which attain highest differentiation in the human brain. Our data show that Reelin-expression in the pallium is evolutionarily conserved and independent of a cortical hem, and suggest that p73 in the cortical hem may be involved in the evolutionary increase in number and complexity of the mammalian neocortical CR cells.

Animals↗
PubMed2000

[Corticohistogenesis and Reelin signal cascade].

Corticohistogenesis follows highly regulated spatial and temporal patterns of cell proliferation, neuronal migration and neuronal differentiation to generate the characteristic cortical layers. We gained several insights into the mechanisms of the processes how a class of neurons attains an appropriate layer in developing neocortex. Using a neurological mutant mice reeler, we identified that the extracellular matrix protein Reelin that is specifically secreted from the Cajal-Retzius cells regulates the positioning of the cortical plate neurons. There has identified that Dab1 is one of the intracellular signaling components that respond to Reelin. Recently, three membrane proteins, apoER2, VLDLR and CNR are identified to bind Reelin. The double mutant--apoER2-/-; vldlr-/(-)--shows a phenotype indistinguishable from Reelin deficient mice. The CNRs are originally isolated through the interaction of their intracellular domain with Fyn, a member of the Src kinase family. The antibodies against Reelin or CNR disrupted Reelin-CNR binding. These three classes of membrane proteins are thought to act in concert as components of the Reelin receptor.

Animals↗