Reeler

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A reeler mouse

A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by the profound underdevelopment of the mouse's cerebellum, a segment of the brain responsible for locomotion. The mutation is autosomal and recessive, and prevents the typical cerebellar folia from forming.

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Cortical neurons are generated normally but are abnormally placed, resulting in disorganization of cortical laminar layers in the central nervous system. 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. [1] In the dentate gyrus of hippocampus, no characteristic radial glial scaffold is formed and no compact granule cell layer is established. [2] 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:

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:

Brain slices of wildtype and reeler mice Reeler lamination.png
Brain slices of wildtype and reeler mice

Key pathological findings in the reeler brain structure

Corticogenesis in a wild-type mouse. First neurons to take their place are the subplate neurons (yellow). Next come the cortical plate neurons (black), which migrate past the subplate level. Later-generated neurons drawn to be increasingly more bright. Corticogenesis in a wild-type mouse with captions in english copy.png
Corticogenesis in a wild-type mouse. First neurons to take their place are the subplate neurons (yellow). Next come the cortical plate neurons (black), which migrate past the subplate level. Later-generated neurons drawn to be increasingly more bright.
Corticogenesis in a reeler mutant mouse. Note the so-called "inverted cortex", disorganized cellular layers, oblique angles of radial glia fibers. Corticogenesis in reeler mutant mouse with captions in english.png
Corticogenesis in a reeler mutant mouse. Note the so-called "inverted cortex", disorganized cellular layers, oblique angles of radial glia fibers.

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. [15]

The mice have reduced density of parvalbumin-containing interneurons in circumscribed regions of striatum, according to one study. [16]

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. [17] 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. [18]

See also

Related Research Articles

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The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis. It docks to the intracellular part of the Reelin very low density lipoprotein receptor (VLDLR) and apoE receptor type 2 (ApoER2) and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation. In mice, Dab1 mutation results in the scrambler mouse phenotype.

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References

  1. ↑ Hartfuss E, Forster E, Bock HH, Hack MA, Leprince P, Luque JM, Herz J, Frotscher M, Gotz M (2003). "Reelin signaling directly affects radial glia morphology and biochemical maturation". Development. 130 (19): 4597–609. doi: 10.1242/dev.00654 . hdl: 10261/333510 . PMID   12925587.
  2. ↑ Weiss KH, Johanssen C, Tielsch A, Herz J, Deller T, Frotscher M, Förster E (2003). "Malformation of the radial glial scaffold in the dentate gyrus of reeler mice, scrambler mice, and ApoER2/VLDLR-deficient mice". J. Comp. Neurol. 460 (1): 56–65. doi:10.1002/cne.10644. PMID   12687696. S2CID   25876741.
  3. ↑ Royaux I, Bernier B, Montgomery JC, Flaherty L, Goffinet AM (1997). "Reln(rl-Alb2), an allele of reeler isolated from a chlorambucil screen, is due to an IAP insertion with exon skipping". Genomics. 42 (3): 479–82. doi:10.1006/geno.1997.4772. PMID   9205121.
  4. ↑ Lalonde R, Hayzoun K, Derer M, Mariani J, Strazielle C (2004). "Neurobehavioral evaluation of Reln-rl-orl mutant mice and correlations with cytochrome oxidase activity". Neurosci. Res. 49 (3): 297–305. doi:10.1016/j.neures.2004.03.012. PMID   15196778. S2CID   46367217.
  5. ↑ Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer RE, Richardson JA, Herz J (June 1999). "Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2". Cell. 97 (6): 689–701. doi: 10.1016/S0092-8674(00)80782-5 . PMID   10380922.
  6. ↑ Kuo G, Arnaud L, Kronstad-O'Brien P, Cooper JA (September 2005). "Absence of Fyn and Src causes a reeler-like phenotype". J. Neurosci. 25 (37): 8578–86. doi: 10.1523/JNEUROSCI.1656-05.2005 . PMC   6725670 . PMID   16162939.
  7. ↑ Park TJ, Curran T (December 2008). "Crk and CrkL play essential overlapping roles downstream of Dab1 in the Reelin pathway". J. Neurosci. 28 (50): 13551–62. doi:10.1523/JNEUROSCI.4323-08.2008. PMC   2628718 . PMID   19074029.
  8. ↑ Molnár Z, Blakemore C (1992). "How are thalamocortical axons guided in the reeler mouse?". Soc. Neurosci. Abstr. 18: 778.
  9. ↑ Molnár Z, Blakemore C (1995). "How do thalamic axons find their way to the cortex?". Trends Neurosci. 18 (9): 389–397. doi:10.1016/0166-2236(95)93935-q. PMID   7482804. S2CID   33802783.
  10. ↑ Molnar Z, Adams R, Goffinet AM, Blakemore C (1998). "The role of the first postmitotic cortical cells in the development of thalamocortical innervation in the reeler mouse". J. Neurosci. 18 (15): 5746–65. doi: 10.1523/jneurosci.18-15-05746.1998 . PMC   6793036 . PMID   9671664.
  11. ↑ Liu Y, Fujise N, Kosaka T (1996). "Distribution of calretinin immunoreactivity in the mouse dentate gyrus. I. General description. Exp". Brain Res. 108 (3): 389–403. doi:10.1007/bf00227262. PMID   8801119. S2CID   13329866.
  12. ↑ Drakew A, Deller T, Heimrich B, Gebhardt C, Del Turco D, Tielsch A, Förster E, Herz J, Frotscher M (2002). "Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice". Exp. Neurol. 176 (1): 12–24. doi:10.1006/exnr.2002.7918. PMID   12093079. S2CID   35575194.
  13. ↑ Niu S, Renfro A, Quattrocchi CC, Sheldon M, D'Arcangelo G (Jan 2004). "Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway". Neuron. 41 (1): 71–84. doi: 10.1016/s0896-6273(03)00819-5 . PMID   14715136.
  14. ↑ Matsuzaki H, Minabe Y, Nakamura K, Suzuki K, Iwata Y, Sekine Y, Tsuchiya KJ, Sugihara G, Suda S, Takei N, Nakahara D, Hashimoto K, Nairn AC, Mori N, Sato K (2007). "Disruption of reelin signaling attenuates methamphetamine-induced hyperlocomotion". Eur. J. Neurosci. 25 (11): 3376–84. doi:10.1111/j.1460-9568.2007.05564.x. PMID   17553006. S2CID   42457893.
  15. ↑ Hadj-Sahraoui N, Frederic F, Delhaye-Bouchaud N, Mariani J (1996). "Gender effect on Purkinje cell loss in the cerebellum of the heterozygous reeler mouse". J. Neurogenet. 11 (1–2): 45–58. doi:10.3109/01677069609107062. PMID   10876649.
  16. ↑ Ammassari-Teule M, Sgobio C, Biamonte F, Marrone C, Mercuri NB, Keller F (March 2009). "Reelin haploinsufficiency reduces the density of PV+ neurons in circumscribed regions of the striatum and selectively alters striatal-based behaviors". Psychopharmacology . 204 (3): 511–21. doi:10.1007/s00213-009-1483-x. PMID   19277610. S2CID   24861541.
  17. ↑ Falconer, D. S. (1951). "Two new mutants, 'trembler' and 'reeler', with neurological actions in the house mouse (Mus musculus L.)". Journal of Genetics. 50 (2): 192–205. doi:10.1007/BF02996215. PMID   24539699. S2CID   37918631.
  18. ↑ D'Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T (1995). "A protein related to extracellular matrix proteins deleted in the mouse mutant reeler". Nature. 374 (6524): 719–723. Bibcode:1995Natur.374..719D. doi:10.1038/374719a0. PMID   7715726. S2CID   4266946.
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