Orleans mutation, 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:
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.
* 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.
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 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. The mice have reduced density of parvalbumin-containing interneurons in circumscribed regions of striatum, according to one study. Studies reveal a 16% deficit in the number of Purkinje cells in 3-month-old and a 24% one in 16-month-old animals: surprisingly this deficit is only present in the 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. In 1995, the RELN gene and reelin protein were discovered at chromosome 7q22 by Tom Curran and colleagues.
