Key Points
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Reeler mice were the first animal mutants to be described with malformations of the cerebral cortex. Interest in these mice increased further after the cloning of the affected gene, which was named reelin (Reln).
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Neuronal migration is initially normal in the brains of reeler mice, but it seems that some cells do not recognize their proper location and orientation at the end of their migration pathway. The defect is most severe in the cerebral cortex, hippocampus and cerebellar cortex, but subtle anomalies have been identified at every location that has been searched.
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Reln is secreted by some neurons, such as Cajal–Retzius cells in the cortical marginal zones, and cerebellar granule cells, and it acts through the extracellular milieu on neighbouring target cells to provide an architectonic signal.
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Reception of the Reln signal requires the presence of at least one of two receptors of the lipoprotein receptor family — the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (ApoER2). The signal is relayed by tyrosine phosphorylation of an intracellular adaptor named Disabled 1 (Dab1).
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The Reln protein is cleaved at two main locations, and almost no full length Reln is detected in adult and embryonic brain extracts and body fluids. The main polypeptides are the amino-terminal 180 kDa and the carboxy-terminal 100 kDa fragments. However, the central region of Reln is essential for receptor binding and triggering of Dab1 phosphorylation.
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The dissection of the Reln signaling network is proving to be difficult, because it does not seem to conform to any known model. However, progress was recently made on two fronts — the interactions between Reln and its receptors, and the characterization of tyrosine kinases that have been implicated in Dab1 phosphorylation.
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The cellular action of Reln during radial neuronal migration is unclear, but it has been proposed that it might act as a 'stop' signal for neurons at the end of their migration pathway. It has also been indicated that it regulates nucleokinesis — the progression of the nucleus into the cytoplasmic furrow that results from extension of the leading edge of a migrating cell.
Abstract
Over the last 50 years, the reeler mutant mouse has become an important model for studying normal and abnormal development in the cerebral cortex and other regions of the brain. However, we are only just beginning to understand the actions of reelin — the protein that is affected by the reeler mutation — at the molecular and cellular level. This review discusses the most recent advances in this research field, and considers the merits of the various models that have been put forward to explain how reelin works.
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Acknowledgements
We wish to thank C. Lambert de Rouvroit for her help in the preparation of this review, as well as I. Bar, Y. Jossin and N. Ignatova for discussions and inclusion of unpublished results. We apologize to colleagues for the inevitable selection of citations due to space limitations. This work was supported by the Fondation Médicale Reine Elisabeth, and by the fifth framework program of the European Union.
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Glossary
- LISSENCEPHALY
-
Literally meaning 'smooth brain'. Lissencephaly is a human brain disorder that is characterized by absence or reduction of the cerebral convolutions.
- VENTRICULAR ZONE
-
The proliferative inner layer of the developing brain and spinal cord.
- SUBVENTRICULAR ZONE
-
A layer of cells in the developing brain that is generated by the migration of neuroblasts from the adjoining ventricular zone.
- RHOMBIC LIP
-
A specialized germinal matrix located at the posterior edge of the cerebellar anlage that gives rise to the granule cells of the cerebellum.
- TATA BOX
-
A DNA sequence with the consensus TATAAAA that is present in many eukaryotic gene promoters and specifies the site where transcription is initiated.
- 5′RACE
-
(5′ rapid amplification of cDNA ends). RACE is a PCR-based method for amplifying unknown cDNA sequences by using primers that correspond to a known sequence.
- ALTERNATIVE SPLICING
-
During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing allows the production of different messages from the same DNA molecule.
- METALLOPROTEINASE
-
A proteinase that has a metal ion at its active site.
- β-PROPELLER
-
A protein domain that consists of an array of β-sheet motifs, which are configured in a ring to resemble the blades of a propeller.
- CAVEOLAE
-
Specialized rafts that contain the protein caveolin and form a flask-shaped, cholesterol-rich invagination of the plasma membrane. They might mediate the uptake of some extracellular materials and are probably involved in cell signalling.
- LIPID RAFTS
-
Cholesterol-rich lipid domains that are used to transport proteins around the cell and to organize signalling complexes on the membrane.
- HYPOMORPHIC ALLELE
-
An allele that results in a reduction, but not the elimination, of wild-type levels of gene product or activity, often causing a less severe phenotype than a loss-of-function (or null) allele.
- HEPARAN SULPHATE
-
A glycosaminoglycan that consists of repeated units of hexuronic acid and glucosamine residues. It usually attaches to proteins through a xylose residue to form proteoglycans.
- YEAST TWO-HYBRID SCREENS
-
System used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; for example, one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, then the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.
- SOMAL TRANSLOCATION
-
Displacement of the cell body, as opposed to migration of the whole cell.
- BLASTOCYST INJECTION
-
The introduction of embryonic stem cells into a blastocyst-stage embryo of a different genotype to generate a chimaeric embryo.
- MORULA AGGREGATION
-
A technique in which the cells of two different embryos at the morula stage (when the embryo comprises a solid ball of cells) are dissociated, mixed and allowed to recombine to generate a chimaeric embryo.
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Tissir, F., Goffinet, A. Reelin and brain development. Nat Rev Neurosci 4, 496–505 (2003). https://doi.org/10.1038/nrn1113
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DOI: https://doi.org/10.1038/nrn1113
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