Recent progress in understanding the role of Reelin in radial neuronal migration, with specific emphasis on the dentate gyrus

Förster, Eckart; Jossin, Yves; Zhao, Shanting; Chai, Xuejun; Frotscher, Michael; Goffinet, André M.

doi:10.1111/j.1460-9568.2006.04612.x

Cited by 104 publications

(71 citation statements)

References 95 publications

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“…For cells to respond to Reelin, they must express not only the appropriate cell surface receptors but also the obligatory signal transducing protein Dab1 Sheldon et al, 1997;Förster et al, 2006). Interestingly, Dab1 mRNA is expressed in layer II pyramidal neurons of the developing entorhinal cortex (Meyer et al, 2003), and we detected both Reelin and Dab1 immunoreactivities in these neurons in the adult mouse brain (data not shown).…”

Section: Discussionmentioning

confidence: 77%

Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease

Chin¹,

Massaro²,

Palop³

et al. 2007

J. Neurosci.

168

132

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Reelin regulates nervous system development and modulates synaptic plasticity in the adult brain. Several findings suggest that alterations in Reelin signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD). Cell surface receptors for Reelin, including integrins and very-low-density lipoprotein receptor/apolipoprotein E2 receptor, may be targets of amyloid-␤ (A␤) peptides presumed to play key roles in the pathogenesis of AD. Reelin also regulates the extent of tau phosphorylation. Finally, increased amounts of Reelin fragments have been found in CSF from AD patients, suggesting altered processing of Reelin. We therefore hypothesized that Reelin levels might be altered in the brains of human amyloid precursor protein (hAPP) transgenic mice, particularly in brain regions vulnerable to AD such as hippocampus and entorhinal cortex. Compared with nontransgenic controls, hAPP mice had significantly fewer Reelin-expressing pyramidal cells in the entorhinal cortex, the major population of glutamatergic neurons expressing Reelin in the brain. Western blot analysis of the hippocampus, which receives projections from the entorhinal cortex, revealed significant reductions in Reelin levels. In contrast, the number of Reelin-expressing GABAergic interneurons was not altered in either the entorhinal cortex or the hippocampus. Thus, neuronal expression of hAPP/A␤ is sufficient to reduce Reelin expression in a specific population of entorhinal cortical pyramidal neurons in vivo. Underscoring the relevance of these findings, we found qualitatively similar reductions of Reelin-expressing pyramidal neurons in the entorhinal cortex of AD brains. We conclude that alterations in Reelin processing or signaling may be involved in AD-related neuronal dysfunction.

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Section: Discussionmentioning

confidence: 77%

Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease

Chin¹,

Massaro²,

Palop³

et al. 2007

J. Neurosci.

168

132

View full text Add to dashboard Cite

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“…However, until now these interactions of Caspr with other molecules have been viewed mainly in the context of neuron-glia interactions at the node of Ranvier. As a third player in the neurite outgrowth regulating activities of PrP and Caspr, we introduce Reelin, an extracellular matrix glycoprotein that has been studied in terms of dendrite and axon development and neurogenesis (Hack et al, 2002;Kim et al, 2002;Niu et al, 2004;Forster et al, 2006;Won et al, 2006;Lorenzetto et al, 2008). A relation to neurite outgrowth for Reelin is again indicated by its capacity to interact with integrins (Dulabon et al, 2000;Schmid et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Cellular Form of Prion Protein Inhibits Reelin-Mediated Shedding of Caspr from the Neuronal Cell Surface to Potentiate Caspr-Mediated Inhibition of Neurite Outgrowth

Devanathan

Jakovčevski

Santuccione

et al. 2010

Journal of Neuroscience

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Extension of axonal and dendritic processes in the CNS is tightly regulated by outgrowth-promoting and -inhibitory cues to assure precision of synaptic connections. We identify a novel role for contactin-associated protein (Caspr) as an inhibitory cue that reduces neurite outgrowth from CNS neurons. We show that proteolysis of Caspr at the cell surface is regulated by the cellular form of prion protein (PrP), which directly binds to Caspr. PrP inhibits Reelin-mediated shedding of Caspr from the cell surface, thereby increasing surface levels of Caspr and potentiating the inhibitory effect of Caspr on neurite outgrowth. PrP deficiency results in reduced levels of Caspr at the cell surface, enhanced neurite outgrowth in vitro, and more efficient regeneration of axons in vivo following spinal cord injury. Thus, we reveal a previously unrecognized role for Caspr and PrP in inhibitory modulation of neurite outgrowth in CNS neurons, which is counterbalanced by the proteolytic activity of Reelin.

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“…We were, however, intrigued that RELN was the most strongly downregulated gene in mutant SCA7 astrocytes. Reelin is primarily expressed in the brain and was originally characterized through its role in the direction of neuronal migration and positioning during development (14,28,29); however, it has also been shown to play a number of roles in the adult brain, including maintenance of the cerebellar PC layer and synaptic connections in the retina (16,30), modulation of neuronal glutamate receptor activity (31), direction of neuronal migration (14,32), and regulation of synaptic plasticity (33). Interestingly, the cerebellar pathology and general phenotype observed in RELN mutant mice are remarkably similar to those of transgenic SCA7 mice (4); yet, further studies would be needed to examine the role of polyQ ATXN7 during development, as well as the role of RELN deficiency in the maintenance of PCs in adults before a more substantial correlation could be made.…”

Section: Discussionmentioning

confidence: 99%

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

McCullough

Dent

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder that results from polyglutamine expansion of the ataxin-7 (ATXN7) protein. Remarkably, although mutant ATXN7 is expressed throughout the body, pathology is restricted primarily to the cerebellum and retina. One major goal has been to identify factors that contribute to the tissue specificity of SCA7. Here we describe the development and use of a human astrocyte cell culture model to identify reelin, a factor intimately involved in the development and maintenance of Purkinje cells and the cerebellum as a whole, as an ATXN7 target gene. We found that polyglutamine expansion decreased ATXN7 occupancy, which correlated with increased levels of histone H2B monoubiquitination, at the reelin promoter. Treatment with trichostatin A, but not other histone deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mutant ATXN7 into nuclear inclusions. Our findings suggest that reelin could be a previously unknown factor involved in the tissue specificity of SCA7 and that trichostatin A may ameliorate deleterious effects of the mutant ATXN7 protein by promoting its sequestration away from promoters into nuclear inclusions.chromatin | SAGA complex | histone modification A s a member of the polyglutamine expansion disorder family, Spinocerebellar ataxia type 7 (SCA7) is an autosomaldominant hereditary disease characterized by cerebellar and retinal degeneration eventually leading to death (1). Although the ataxin-7 (ATXN7) protein is expressed throughout the body, pathology is localized primarily within the cerebellum and retina. Cerebellar Purkinje cell (PC) degeneration is an integral step in the development and progression of SCA7 and has been observed in several independent transgenic mouse models of the disease (2-5); however, increasing evidence indicates that glial cell dysfunction contributes significantly to polyglutamine expansion disorder pathology (2, 6, 7). Interestingly, two distinct SCA7 mouse models exhibit non-cell-autonomous neurodegeneration (2, 4). Of these, the model used by Custer et al. (2) demonstrates that astrocyte-specific expression of polyQ ATXN7, via the Gfa2 promoter (8), results in PC degeneration and the onset of SCA7 symptoms. Astrocytes play a crucial role in the regulation of synaptic formation and function by ensheathing axon-dendrite connections to form a structure known as the tripartite synapse (9). This intimate interaction allows astrocytes to modulate synaptic function through the release of chemical messengers and the regulation of neurotransmitter and ion concentration within the synapse (9-11). The identification of tissue specificity factors and characterization of associated molecular mechanisms involved in their deregulation will facilitate a more comprehensive understanding of disease-associated events and advance efforts to develop effective treatments.The ATXN7 protein is an integral subunit of GCN5 (general control of amino acid synthesis-5; KAT2A)...

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Recent progress in understanding the role of Reelin in radial neuronal migration, with specific emphasis on the dentate gyrus

Cited by 104 publications

References 95 publications

Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease

Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease

Cellular Form of Prion Protein Inhibits Reelin-Mediated Shedding of Caspr from the Neuronal Cell Surface to Potentiate Caspr-Mediated Inhibition of Neurite Outgrowth

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

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