Attenuation of Notch signaling promotes the differentiation of neural progenitors into neurons in the hippocampal CA1 region after ischemic injury

Oya, Soichi; Yoshikawa, Gakushi; Takai, Keisuke; Tanaka, Junichi; Higashiyama, Shigeki; Saito, Nobuhito; Kirino, Takaaki; Kawahara, Nobutaka

doi:10.1016/j.neuroscience.2008.10.043

Cited by 55 publications

(40 citation statements)

References 34 publications

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“…Notch signaling plays an essential role in maintaining NSCs (1,23). Its downregulation promotes neurogenesis during development or in the adult stage (40,55). Our finding that miR- on May 11, 2018 by guest http://mcb.asm.org/ 146a targets Notch1 expression suggests that miR-146a may regulate NSC behavior.…”

Section: Egfr Activation and Pten Inactivation Synergistically Inducementioning

confidence: 81%

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Mei

Bachoo²,

Zhang³

2011

Molecular and Cellular Biology

159

131

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Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation (EGFR vIII ), in combination with the dual inactivation of INK4A/ARF and PTEN, is a leading cause of gliomagenesis. Our global expression analysis for microRNAs revealed that EGFR activation induces miR-146a expression, which is further potentiated by inactivation of PTEN. Unexpectedly, overexpression of miR-146a attenuates the proliferation, migration, and tumorigenic potential of Ink4a/Arf ؊/؊ Pten ؊/؊ Egfr vIII murine astrocytes. Its ectopic expression also inhibits the glioma development of a human glioblastoma cell line in an orthotopic xenograft model. Such an inhibitory function of miR-146a on gliomas is largely through downregulation of Notch1, which plays a key role in neural stem cell maintenance and is a direct target of miR-146a. Accordingly, miR-146a modulates neural stem cell proliferation and differentiation and reduces the formation and migration of glioma stem-like cells. Conversely, knockdown of miR-146a by microRNA sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes. These findings indicate that, in response to oncogenic cues, miR-146a is induced as a negative-feedback mechanism to restrict tumor growth by repressing Notch1. Our results provide novel insights into the signaling pathways that link neural stem cells to gliomagenesis and may lead to new strategies for treating brain tumors.Gliomas are the most frequently observed brain tumors, with glioblastoma multiforme (GBM) being the most common and aggressive form in adults (35). Despite major therapeutic improvements made by combining neurosurgery, chemotherapy, and radiotherapy, the prognosis and survival rate for patients with GBM is still extremely poor (7). The deadly nature of GBM originates from explosive growth and invasive behavior, which are fueled by dysregulation of multiple signaling pathways. Epidermal growth factor receptor (EGFR) activation, in cooperation with loss of tumor suppressor functions, such as mutations in Ink4a/Arf and Pten genes, constitutes a lesion signature for GBM (4). Such dysregulated genetic pathways are sufficient to transform neural stem cells (NSCs) or astrocytes into cancer stem-like cells. This gives rise to highgrade malignant gliomas with a pathological phenotype resembling human GBM (5, 59). However, the downstream events underlying these genetic dysregulations in gliomagenic cells have not been fully elucidated.MicroRNAs are 20-to 22-nucleotide noncoding RNA molecules that have emerged as key players in controlling NSC self-renewal and differentiation (11,57). Aberrant expression of miRNAs, such as miR-21, miR-124, and miR-137, is linked to glioma formation (49). miR-199b-5p and miR-34a impair cancer stem-like cells through the negative regulation of several components of the Notch pathway in brain tumors (18,21). The Notch pathway is an evolutionarily conserved signaling pathway that plays an important role in neurogenesis (3, 10, 23). Upon bindi...

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Section: Egfr Activation and Pten Inactivation Synergistically Inducementioning

confidence: 81%

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Mei

Bachoo²,

Zhang³

2011

Molecular and Cellular Biology

159

131

View full text Add to dashboard Cite

show abstract

“…Recent data have demonstrated that Notch is also expressed in the adult mammalian hippocampus and anterior subventricular zone (aSVZ) (Givogri et al, 2006). Based on these previous studies, Oya et al (2009) investigated the role of Notch signaling in the hippocampal CA1 region after transient global ischemia in rats, and found that the attenuation of Notch signaling in the subacute phase enhanced neuronal regeneration. It remains unclear whether Notch has any further effects during the later stages of differentiation and maturation.…”

Section: Nscs and Huwe1mentioning

confidence: 99%

Short Communication Huwe1 as a therapeutic target for neural injury

et al. 2014

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“…In addition, Notch activation has been shown to be essential in neural stem cell proliferation in several hypoxia-ischemia rodent models (Androutsellis-Theotokis et al, 2006;Carlen et al, 2009;Chen et al, 2008a;Oya et al, 2009;Wang et al, 2009). Canonical Notch signaling is activated through a hypoxia-dependent mechanism (Johnson, 2011;Seidel et al, 2010), as well as through overexpression of the ligand (Androutsellis- Theotokis et al, 2006;Liu et al, 2011).…”

Section: Notch In Ischemic Injurymentioning

confidence: 99%

“…Neural stem cells of the SGZ and SVZ, which are quiescent under physiological conditions, have been shown to proliferate following injury (Kawai et al, 2005;Lugert et al, 2010), probably in an attempt to repair brain damage. Notch signaling, which is a known neurogenic factor (Gaiano and Fishell, 2002), has been shown to be central in this process, as demonstrated by genetic and chemical loss of function models (Kawai et al, 2005;Oya et al, 2009;Wang et al, 2009;Xin et al, 2006). Interestingly, this regenerative potential, in response to injury, is diminished with aging (Lugert et al, 2010).…”

Section: Notch In Ischemic Injurymentioning

confidence: 99%

“…Some time after stroke, attenuation of Notch signaling appears to be required for integration of newly born neurons in the hippocampal network (Oya et al, 2009). On the other hand, a recent report has shown that 1 week after kainate injury, Notch-dependent stem cell proliferation is short-lived and cell fate commitment, mainly of astroglial type, occurs (Sibbe et al, 2012).…”

Section: Notch In Ischemic Injurymentioning

confidence: 99%

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