||This article may be too technical for most readers to understand. (September 2009)|
A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by profound hypoplasia of the mouse's cerebellum, in which the normal cerebellar folia are missing. The mutation is autosomal and recessive.
Cortical neurons are generated normally but are abnormally placed, resulting in disorganization of cortical laminar layers in the CNS. The reason is the lack of Reelin, an extracellular matrix glycoprotein, which during the corticogenesis is secreted mainly by the Cajal-Retzius cells. In the reeler neocortex, cortical plate neurons are aligned in a practically inverted fashion (‘‘outside-in’’). In the ventricular zone of the cortex fewer neurons have been found to have radial glial processes. In the dentate gyrus of hippocampus, no characteristic radial glial scaffold is formed and no compact granule cell layer is established. Therefore, the reeler mouse presents a good model in which to investigate the mechanisms of establishment of the precise neuronal network during development.
Types of reelers
There are two types of the reeler mutation:
- Albany2 mutation (Reln(rl-Alb2)
- Orleans mutation (Reln-rl-orl, or rl-orl), in which reelin lacks a C-terminal region and a part of the eighth reelin repeat. This hampers the secretion of the protein from the cell.
In order to unravel the reelin signaling chain, attempts are made to cut the signal downstream of reelin, leaving reelin expression intact but creating the reeler phenotype, sometimes a partial phenotype, thus confirming the role of downstream molecules. The examples include:
- Double knockout of VLDLR and ApoER2 receptors;
- Double knockout of Src and Fyn kinases.
- Cre-loxP recombination mice model that lacks Crk and CrkL in most neurons. Was used to show that Crk/CrkL lie downstream of DAB1] in the reelin signaling pathway.
- Scrambler mouse
Key pathological findings in the Reeler brain structure
- Inversion of cortical layers.
- Subplate cells become abnormally located in the subpial zone above the cortical plate. This hampers their function in establishing the transient circuits between the incoming thalamic axons and layer IV cells of the cortical plate. Thalamic axons have to grow past the cortical plate to reach the mispositioned subplate cells in the so-called superplate and then turn back down to contact their appropriate targets. This creates a curious "looping" thalamocortical connection seen in the adult reeler brain.
- Dispersion of neurons within cortical layers.
- Decreased cerebellar size.
- Failure of preplate to split
- Failure to establish a distinct granule cell layer in the dentate gyrus. Normal dentate gyrus demonstrates a clear segregation of granule cells and hilar mossy cells, which are identified, respectively, by their expression of calbindin and calretinin. In the reeler DG, the two cell types intermingle.
- Impaired dendrite outgrowth.
- In one study, reeler mice were shown to have attenuated methamphetamine-induced hyperlocomotion, which was also reduced by a targeted disruption of reelin activity in wildtype mice. Reeler mice in the same study demonstrated a decrease in D1 and D2 receptor-mediated dopaminergic function together with reduced numbers of D1\D2 receptors. 
Heterozygous Reeler Mouse
Heterozygous reeler mice, also known as HRM, while lacking the apparent phenotype seen in the homozygous reeler, also show some brain abnormalities due to the reelin deficit.
Heterozygous (rl/+) mice express reelin at 50% of wild-type levels and have grossly normal brains but exhibit a progressive loss during aging of a neuronal target of reelin action, Purkinje cells.
Studies reveal a 16% deficit in the number of Purkinje cells in 3-month-old (+/rl) and a 24% one in 16-month-old animals: surprisingly this deficit is only present in the (+/rl) males, while the females are spared.
History of research
First mention of reeler mouse mutation dates back to 1951. In the later years, histopathological studies revealed that the reeler cerebellum is dramatically decreased in size and the normal laminar organization found in several brain regions is disrupted (Hamburgh, 1960). In 1995, the RELN gene and reelin protein were discovered at chromosome 7q22 by Tom Curran and colleagues.
- Shaking rat Kawasaki has a reduced reelin expression due to missplicing of the reelin gene.
- Sticky mouse
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- Development of the Cerebral Cortex: III. The Reeler Mutation - by Paul J. Lombroso, M.D.