Reelin affects chain-migration and differentiation of neural precursor cells

Massalini, Simone; Pellegatta, Serena; Pisati, Federica; Finocchiaro, Gaetano; Farace, Maria Giulia; Ciafrè, Silvia Anna

doi:10.1016/j.mcn.2009.08.006

Cited by 30 publications

(22 citation statements)

References 42 publications

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“…The capacity of reelin to regulate cell proliferation, migration, and differentiation agrees with observations made in neural [29][30][31] and non-neural tissues, such as submandibular 32 and mammary gland. 33 However, inhibition of cell migration in primary cultures of mammary epithelial cells 33 and of apoptosis in embryonic carcinoma cells 34 by exogenous reelin have also been reported.…”

Section: -21supporting

confidence: 86%

“…50 (4) The absence of reelin reduces the intestinal expression of a large number of genes that code for proteins involved in the intestinal immune response, inflammation, and cancer processes. 17 As several reports have proposed a role for reelin in tissue repair in both, neural 31,[51][52][53] and nonneural tissues, 32,51,54 its involvement in the activation of cell proliferation and migration during the mucosal regenerative response triggered by injury could not be discarded.…”

Section: -21mentioning

confidence: 99%

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Reelin Is Involved in the Crypt-Villus Unit Homeostasis

García‐Miranda

Vázquez‐Carretero

Sesma

et al. 2013

Tissue Engineering Part A

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Intestinal myofibroblasts secrete substances that control organogenesis and wound repair of the intestine. The myofibroblasts of the rat small intestine express reelin and the present work explores whether reelin regulates crypt-villus unit homeostasis using normal mice and mice with the reelin gene disrupted (reeler). The results reveal that mouse small intestine expresses reelin, its receptors apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VldlR) and the reelin effector protein Disabled-1 (Dab1) and that reelin expression is restricted to myofibroblasts. The absence of reelin significantly reduces epithelial cell proliferation, migration, and apoptosis and the number of Paneth cells. These effects are observed during the suckling, weaning, and adult periods. The number of Goblet cells is increased in the 2-month-old reeler mice. The absence of reelin also expands the extracellular space of the adherens junctions and desmosomes without significantly affecting either the tight-junction structure or the epithelial paracellular permeability. In conclusion, this is the first in vivo work showing that the absence of reelin alters intestinal epithelium homeostasis.

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Section: -21supporting

confidence: 86%

Section: -21mentioning

confidence: 99%

Reelin Is Involved in the Crypt-Villus Unit Homeostasis

García‐Miranda

Vázquez‐Carretero

Sesma

et al. 2013

Tissue Engineering Part A

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“…Together with previously published results (Hartfuss et al, 2003;Anthony et al, 2005;Keilani and Sugaya, 2008;Gaiano, 2008), they are consistent with the notion of reelin acting upstream of Notch signaling in NPCs to regulate cell fate before differentiation. Our results also emphasize the need for combined GOF and LOF approaches, as conflicting results have been obtained in two reports upon differentiation of reeler-derived neurospheres (Kwon et al, 2009;Massalini et al, 2009). The recent proposal that Dab1 suppresses astroglial differentiation, albeit independently of reelin (Kwon et al, 2009), is seemingly incompatible with previously published results showing how the lack of reelin accelerates the transition of radial glial cells to astrocytes (Hunter-Schaedle, 1997) and our own observations showing reciprocal behavior in the reelin GOF condition (supplementary material Fig.…”

Section: Research Articlesupporting

confidence: 58%

Reelin sets the pace of neocortical neurogenesis

2011

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SUMMARYMigration of neurons during cortical development is often assumed to rely on purely post-proliferative reelin signaling. However, Notch signaling, long known to regulate neural precursor formation and maintenance, is required for the effects of reelin on neuronal migration. Here, we show that reelin gain-of-function causes a higher expression of Notch target genes in radial glia and accelerates the production of both neurons and intermediate progenitor cells. Converse alterations correlate with reelin lossof-function, consistent with reelin controlling Notch signaling during neurogenesis. Ectopic expression of reelin in isolated clones of progenitors causes a severe reduction in neuronal differentiation. In mosaic cell cultures, reelin-primed progenitor cells respond to wild-type cells by further decreasing neuronal differentiation, consistent with an increased sensitivity to lateral inhibition. These results indicate that reelin and Notch signaling cooperate to set the pace of neocortical neurogenesis, a prerequisite for proper neuronal migration and cortical layering.

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“…Reelin and GAD 67 play important roles in neuronal differentiation (Massalini et al, 2009) and regulation of neuronal excitability (Hyde and Weinberger, 1997; Daskalakis et al, 2002; Mattay et al, 1997), respectively. Recent studies showed that these two genes are downregulated in GABAergic interneurons overexpressing Dnmt1 in SZ and BP brains (Veldic et al, 2005; Tueting et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Mouse ES cells overexpressing DNMT1 produce abnormal neurons with upregulated NMDA/NR1 subunit

et al. 2011

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High levels of DNA methyltransferase 1 (DNMT1), hypermethylation, and downregulation of GAD67 and reelin have been described in GABAergic interneurons of patients with schizophrenia (SZ) and bipolar (BP) disorders. However, overexpression of DNMT1 is lethal, making it difficult to assess the direct effect of high levels of DNMT1 on neuronal development in vivo. We therefore used Dnmt1tet/tet mouse ES cells that overexpress DNMT1 as an in vitro model to investigate the impact of high levels of DNMT1 on neuronal differentiation. Although there is down-regulation of DNMT1 during early stages of differentiation in wild type and Dnmt1tet/tet ES cell lines, neurons derived from Dnmt1tet/tet cells showed abnormal dendritic arborization and branching. The Dnmt1tet/tet neuronal cells also showed elevated levels of functional N-methyl D-aspartate receptor (NMDAR), a feature also reported in some neurological and neurodegenerative disorders. Considering the roles of reelin and GAD67 in neuronal networking and excitatory/inhibitory balance respectively, we studied methylation of these genes' promoters in Dnmt1tet/tet ES cells and neurons. Both reelin and GAD67 promoters were not hypermethylated in the Dnmt1tet/tet ES cells and neurons, suggesting that overexpression of DNMT1 may not directly result in methylation-mediated repression of these two genes. Taken together, our results suggest that overexpression of DNMT1 in ES cells results in an epigenetic change prior to the onset of differentiation. This epigenetic change in turn results in abnormal neuronal differentiation and upregulation of functional NMDA receptor.

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Reelin affects chain-migration and differentiation of neural precursor cells

Cited by 30 publications

References 42 publications

Reelin Is Involved in the Crypt-Villus Unit Homeostasis

Reelin Is Involved in the Crypt-Villus Unit Homeostasis

Reelin sets the pace of neocortical neurogenesis

Mouse ES cells overexpressing DNMT1 produce abnormal neurons with upregulated NMDA/NR1 subunit

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