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

<span class="mw-page-title-main">Reelin</span> Large secreted extracellular matrix glycoprotein involved in neuronal migration

Reelin, encoded by the RELN gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation. It also stimulates dendrite and dendritic spine development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like the subventricular and subgranular zones. It is found not only in the brain but also in the liver, thyroid gland, adrenal gland, fallopian tube, breast and in comparatively lower levels across a range of anatomical regions.

<span class="mw-page-title-main">Dentate gyrus</span> Region of the hippocampus in the brain

The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute to the formation of new episodic memories, the spontaneous exploration of novel environments and other functions.

<span class="mw-page-title-main">Olfactory bulb</span> Neural structure

The olfactory bulb is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (OFC) and the hippocampus where it plays a role in emotion, memory and learning.

<span class="mw-page-title-main">Thalamocortical radiations</span> Neural pathways between the thalamus and cerebral cortex

In neuroanatomy, thalamocortical radiations, also known as thalamocortical fibers, are the efferent fibers that project from the thalamus to distinct areas of the cerebral cortex. They form fiber bundles that emerge from the lateral surface of the thalamus.

<span class="mw-page-title-main">DAB1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">VLDL receptor</span> Protein-coding gene in the species Homo sapiens

The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle, adipose tissue, and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of apolipoprotein E-containing triacylglycerol-rich lipoproteins, and neuronal migration in the developing brain. In humans, VLDLR is encoded by the VLDLR gene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type I lissencephaly, cerebellar hypoplasia, and atherosclerosis.

The stratum lucidum of the hippocampus is a layer of the hippocampus between the stratum pyramidale and the stratum radiatum. It is the tract of the mossy fiber projections, both inhibitory and excitatory from the granule cells of the dentate gyrus. One mossy fiber may make up to 37 connections to a single pyramidal cell, and innervate around 12 pyramidal cells on top of that. Any given pyramidal cell in the stratum lucidum may get input from as many as 50 granule cells.

<span class="mw-page-title-main">Mossy fiber (hippocampus)</span> Pathway in the hippocampus

In the hippocampus, the mossy fiber pathway consists of unmyelinated axons projecting from granule cells in the dentate gyrus that terminate on modulatory hilar mossy cells and in Cornu Ammonis area 3 (CA3), a region involved in encoding short-term memory. These axons were first described as mossy fibers by Santiago Ramón y Cajal as they displayed varicosities along their lengths that gave them a mossy appearance.

<span class="mw-page-title-main">Low-density lipoprotein receptor-related protein 8</span> Cell surface receptor, part of the low-density lipoprotein receptor family

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans is encoded by the LRP8 gene. ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin, ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation. Another LDL family receptor, VLDLR, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.

<span class="mw-page-title-main">Norman–Roberts syndrome</span> Medical condition

Norman–Roberts syndrome is a rare form of microlissencephaly caused by a mutation in the RELN gene. A small number of cases have been described. The syndrome was first reported by Margaret Grace Norman and M. Roberts et al. in 1976.

<span class="mw-page-title-main">EMX1</span> Protein-coding gene in the species Homo sapiens

Homeobox protein EMX1 is a protein that in humans is encoded by the EMX1 gene. The transcribed EMX1 gene is a member of the EMX family of transcription factors. The EMX1 gene, along with its family members, are expressed in the developing cerebrum. EMX1 plays a role in specification of positional identity, the proliferation of neural stem cells, differentiation of layer-specific neuronal phenotypes and commitment to a neuronal or glial cell fate.

The trisynaptic circuit or trisynaptic loop is a relay of synaptic transmission in the hippocampus. The trisynaptic circuit is a neural circuit in the hippocampus, which is made up of three major cell groups: granule cells in the dentate gyrus, pyramidal neurons in CA3, and pyramidal neurons in CA1. The hippocampal relay involves 3 main regions within the hippocampus which are classified according to their cell type and projection fibers. The first projection of the hippocampus occurs between the entorhinal cortex (EC) and the dentate gyrus (DG). The entorhinal cortex transmits its signals from the parahippocampal gyrus to the dentate gyrus via granule cell fibers known collectively as the perforant path. The dentate gyrus then synapses on pyramidal cells in CA3 via mossy cell fibers. CA3 then fires to CA1 via Schaffer collaterals which synapse in the subiculum and are carried out through the fornix. Collectively the dentate gyrus, CA1 and CA3 of the hippocampus compose the trisynaptic loop.

<span class="mw-page-title-main">Hippocampus anatomy</span> Component of brain anatomy

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Scrambler is a spontaneous mouse mutant lacking a functional DAB1 gene, resulting in a phenotype resembling that seen in the reeler mouse. The strain was first described by Sweet et al. in 1996.

<span class="mw-page-title-main">Cerebellar granule cell</span> Thick granular layer of the cerebellar cortex

Cerebellar granule cells form the thick granular layer of the cerebellar cortex and are among the smallest neurons in the brain. Cerebellar granule cells are also the most numerous neurons in the brain: in humans, estimates of their total number average around 50 billion, which means that they constitute about 3/4 of the brain's neurons.

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Granule cell dispersion is one of the abnormal structural changes that has been shown in brains of patients with temporal lobe epilepsy. It has also been shown in different animal models, such as the kainic acid model, pilocarpine model, and kindling model. But granule cell dispersion was not found by using perforant pathway stimulation.

Cajal–Retzius cells are a heterogeneous population of morphologically and molecularly distinct reelin-producing cell types in the marginal zone/layer I of the developing cerebral cortex and in the immature hippocampus of different species and at different times during embryogenesis and postnatal life.

<span class="mw-page-title-main">AGTPBP1 (gene)</span> Human protein-coding gene

ATP/GTP binding protein 1 is gene that encodes the protein known as cytosolic carboxypeptidase 1 (CCP1), originally named NNA1. Mice with a naturally occurring mutation of the Agtpbp1 gene are known as pcd mice.

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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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