Neurofibromin Regulates Neural Stem Cell Proliferation, Survival, and Astroglial Differentiation In Vitro and In Vivo

Dasgupta, Biplab; Gutmann, David H.

doi:10.1523/jneurosci.4693-04.2005

Cited by 126 publications

(112 citation statements)

References 48 publications

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“…Studies have shown that various Nf1 À/À cell types are more resistant than Nf1 þ / þ cells to apoptosis induced by trophic factor deprivation. 19,29 Therefore, we examined whether Nf1 À/À SV40 MEFs would also be more resistant than Nf1 þ / þ and Nf1 þ /À SV40 MEFs to apoptosis induced by trophic factor deprivation, and if so, whether or not this effect was dependent on Ras. The three Nf1 SV40 MEF genotypes were deprived of serum for 15 h and the numbers of live and dead cells were then determined by counting.…”

Section: Resultsmentioning

confidence: 99%

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

et al. 2006

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Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio-and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1 À/À , Nf1 þ /À , and Nf1 þ / þ MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD-independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.

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Section: Resultsmentioning

confidence: 99%

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

et al. 2006

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“…3g,gЈ). This cellular morphology may indicate astroglial differentiation (Chiang et al, 1996;McManus et al, 1999;Weiss et al, 2003;Dasgupta and Gutmann, 2005;Brunne et al, 2010). In the infrapyramidal blade, most GFAP ϩ or BLBP ϩ cells displayed excessive arborization, suggestive of a transition to an astrocytic fate.…”

Section: Loss Of Foxg1 Results In Malformation Of the Secondary Radiamentioning

confidence: 99%

Foxg1Has an Essential Role in Postnatal Development of the Dentate Gyrus

Tian

Gong²,

Yang³

et al. 2012

J. Neurosci.

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Foxg1, formerly BF-1, is expressed continuously in the postnatal and adult hippocampal dentate gyrus (DG). This transcription factor (TF) is thought to be involved in Rett syndrome, which is characterized by reduced hippocampus size, indicating its important role in hippocampal development. Due to the perinatal death of Foxg1 Ϫ/Ϫ mice, the function of Foxg1 in postnatal DG neurogenesis remains to be explored. Here, we describe the generation of a Foxg1 fl/fl mouse line. Foxg1 was conditionally ablated from the DG during prenatal and postnatal development by crossing this line with a Frizzled9-CreER TM line and inducing recombination with tamoxifen. In this study, we first show that disruption of Foxg1 results in the loss of the subgranular zone and a severely disrupted secondary radial glial scaffold, leading to the impaired migration of granule cells. Moreover, detailed analysis reveals that Foxg1 may be necessary for the maintenance of the DG progenitor pool and that the lack of Foxg1 promotes both gliogenesis and neurogenesis. We additionally show that Foxg1 may be required for the survival and maturation of postmitotic neurons and that Foxg1 may be involved in Reelin signaling in regulating postnatal DG development. Last, prenatal deletion of Foxg1 suggests that it is rarely involved in the migration of primordial granule cells. In summary, we report that Foxg1 is critical for DG formation, especially during early postnatal stage.

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“…Increased Ras in neural stem cells was found to lead to an increase in gliogenesis (45). Rapgef6 expression was positively linked with astrogenesis and negatively linked to neurogenesis.…”

Section: Discussionmentioning

confidence: 95%

Natural variation and genetic covariance in adult hippocampal neurogenesis

Kempermann

Chesler

et al. 2006

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

179

162

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Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB͞BXA, n ‫؍‬ 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1͞CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.gene array ͉ hippocampus ͉ precursor ͉ quantitative trait loci ͉ stem cell N eurogenesis in adult mammals is modulated by complex interactions among genetic and environmental factors. Our goal is to use a systems genetics approach to determine how the development of new neurons and glia is modulated by gene polymorphisms, activity, and environmental stimuli. A first step toward this goal is to analyze natural variation and genetic covariance among key neurogenesis parameters such as proliferation, survival, and differentiation of new cells. We have shown that natural variation is substantial among different strains of mice (1-3). The normal range of variation often exceeds the effects of single gene mutations in engineered lines of mice.In this study, we extended this analysis of normal variation and applied a systems genetics approach to study the covariance structure of four key parameters of adult hippocampal neurogenesis across two large genetic reference populations consisting of a total of 52 recombinant inbred strains. This approach allowed us to exploit covariance of diverse traits to demonstrate biological linkage and pleiotropy (4, 5). The analysis, however, extends beyond a correlative approach. Both of the genetic reference populations used, the BXD and AXB͞BXA sets, are standard mapping panels, making it possible to search for gene loci, so-called quantitative trait loci (QTL), that produce common variation and pleiotropy among traits linked to adult hippocampal neurogenesis.A...

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Neurofibromin Regulates Neural Stem Cell Proliferation, Survival, and Astroglial Differentiation In Vitro and In Vivo

Cited by 126 publications

References 48 publications

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

Foxg1Has an Essential Role in Postnatal Development of the Dentate Gyrus

Natural variation and genetic covariance in adult hippocampal neurogenesis

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