Dentate Granule Cells in Reeler Mutants and VLDLR and ApoER2 Knockout Mice

Drakew, Alexander; Deller, Thomas; Heimrich, Bernd; Gebhardt, Carl; Turco, Domenico Del; Tielsch, Albrecht; Förster, Eckart; Herz, Joachim; Frotscher, Michael

doi:10.1006/exnr.2002.7918

Cited by 84 publications

(89 citation statements)

References 32 publications

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“…Similarly, the proliferation of hippocampal progenitor cells in adult mice was decreased in conditional Notch mutants (Breunig et al, 2007). In Reeler, developmental defects arise as a postnatal lack of a radial glial scaffold and defective granule cell lamination (Stanfield and Cowan, 1979;Drakew et al, 2002; see also this study). We were able to mimic these Reeler-like defects by inactivating Notch signaling with DAPT applied to slice cultures from newborn animals.…”

Section: Notch1 Inhibition Leads To Asupporting

confidence: 55%

“…During this developmental process, Reelin plays a pivotal role. The lack of Reelin in the Reeler mouse leads to severe morphological distortions: namely, the radial glial scaffold fails to form, and granule cells disperse throughout the DG (Drakew et al, 2002;Förster et al, 2002;Frotscher et al, 2003;Weiss et al, 2003). Recently, it has been shown that Reelin and Notch signaling interact in the regulation of neuronal migration and lamination in the cerebral cortex (Hashimoto-Torii et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Wnt signaling and proneural transcription factors such as Neurogenin2 and NeuroD1 are important for granule cell generation and differentiation (Galceran et al, 2000;Lee et al, 2000;Liu et al, 2000;Galichet et al, 2008). Formation of the dentate radial glial scaffold depends on Reelin, and both Reelin and SDF1 control granule cell migration (Bagri et al, 2002;Drakew et al, 2002). Reeler mutants lack Reelin, their radial glial cells undergo precocious astrocytic differentiation, and granule cells show severe migration defects being scattered throughout the dentate gyrus Frotscher et al, 2003;Weiss et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Reelin and Notch1 Cooperate in the Development of the Dentate Gyrus

Sibbe¹,

Förster²,

Basak³

et al. 2009

Journal of Neuroscience

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The development of the hippocampal dentate gyrus is a complex process in which several signaling pathways are involved and likely interact with each other. The extracellular matrix molecule Reelin is necessary both for normal development of the dentate gyrus radial glia and neuronal migration. In Reelin-deficient Reeler mice, the hippocampal radial glial scaffold fails to form, and granule cells are dispersed throughout the dentate gyrus. Here, we show that both formation of the radial glia scaffold and lamination of the dentate gyrus depend on intact Notch signaling. Inhibition of Notch signaling in organotypic hippocampal slice cultures induced a phenotype reminiscent of the Reelin-deficient hippocampus, i.e., a reduced density of radial glia fibers and granule cell dispersion. Moreover, a Reelindependent rescue of the Reeler phenotype was blocked by inhibition of Notch activation. In the Reeler dentate gyrus, we found reduced Notch1 signaling; the activated Notch intracellular domain as well as the transcriptional targets, brain lipid-binding protein, and Hes5 are decreased. Disabled1, a component of the Reelin-signaling pathway colocalizes with Notch1, thus indicating a direct interaction between the Reelin-and Notch1-signaling pathways. These results suggest that Reelin enhances Notch1 signaling, thereby contributing to the formation of the radial glial scaffold and the normal development of the dentate gyrus.

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Section: Notch1 Inhibition Leads To Asupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reelin and Notch1 Cooperate in the Development of the Dentate Gyrus

Sibbe¹,

Förster²,

Basak³

et al. 2009

Journal of Neuroscience

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“…Reduced reelin RNA levels in the dentate gyrus from patients with temporal lobe epilepsy may be related to the degree of granule cell dispersion in this disorder 29,30 and reeler mice have significant disruptions in the architecture of dentate granule cells. 31 Although gross disarray of dentate granule cell architecture has not been reported in severe mental illness, a subtler defect than that seen in epilepsy may be present in schizophrenia, bipolar disorder, and major depression. The dentate granule cells are potentially relevant to all three disease phenotypes as they receive input from the entorhinal cortex and then project to the CA subdivisions of the hippocampus via the mossy fibers.…”

Section: Discussionmentioning

confidence: 99%

Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium

et al. 2004

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Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P ¼ 0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2 A and 5HT1 B receptors, and dopamine D 5 receptors.

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“…While neuronal ectopia is certainly a direct result of a loss in Reelin-Dab1 signaling, there are likely several compounding factors that lead to altered connectivity. The two most obvious factors are the widespread abnormal neuronal orientation and dendritic abnormalities [6,23,27,28]. Proper neuronal orientation, which is established prior to dendritic elongation, is imperative for a neuron to correctly integrate into the local network [17].…”

Section: Neurons Only Need To Receive a Small Amount Of The Reelin-damentioning

confidence: 99%

Hippocampal dendritic arbor growth in vitro: Regulation by Reelin–Disabled-1 signaling

Maclaurin¹,

Krucker²,

Fish³

2007

Brain Research

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The cytoplasmic adaptor protein Disabled-1 (Dab1), which is a key component of the Reelinsignaling pathway, has been suggested to be required for neuronal dendritic development. However, only data from studies on immature cultures [≤ 6 days in vitro (DIV)] and cytoarchitectural analyses of mutant mice have been used to formulate this hypothesis. Therefore, to determine if Reelin-Dab1 signaling is specifically required for neurons to develop mature dendrites in respect to length and complexity we analyzed dendritic development in mature cultures derived from Dab1 knockout (ko) embryos. No significant differences in dendritic length or complexity between Dab1 ko and wt cultures were found at 20 DIV. An examination of dendritic development in maturing cultures found significant differences in dendritic length between mutant and wt cultures at 4 DIV, but detected no differences in complexity. In addition, by 7 DIV all measures were statistically the same between cultures. Therefore, although Reelin-Dab1 signaling promotes hippocampal dendrite development, Dab1 is not required for neurons to reach maturity with respect to dendritic length and complexity. Furthermore, analyses of 4 DIV cultures derived from Dab1 heterozygotes or mice that express only the natural splice form of Dab1 (p45) found that Dab1 p45/− hemizygote, but not Dab1 p45/p45 and Dab1 heterozygote cultures had significantly shorter dendrites than those in wt cultures. Thus, a substantial attenuation of the Reelin-Dab1 signal is required before dendrite elongation is significantly decreased at 4 DIV. Moreover, experiments that incorporated a Reelin-neutralizing antibody support the hypothesis that the role(s) Reelin-signaling plays in dendritic maturation is different than the one it has in neuronal positioning.

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Dentate Granule Cells in Reeler Mutants and VLDLR and ApoER2 Knockout Mice

Cited by 84 publications

References 32 publications

Reelin and Notch1 Cooperate in the Development of the Dentate Gyrus

Reelin and Notch1 Cooperate in the Development of the Dentate Gyrus

Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium

Hippocampal dendritic arbor growth in vitro: Regulation by Reelin–Disabled-1 signaling

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