Essential Roles of Notch Signaling in Maintenance of Neural Stem Cells in Developing and Adult Brains

Imayoshi, Itaru; Sakamoto, Masayuki; Yamaguchi, Masahiro; Mori, Kensaku; Kageyama, Ryoichiro

doi:10.1523/jneurosci.4987-09.2010

Cited by 638 publications

(613 citation statements)

References 58 publications

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“…Therefore, in our model of Rbpjκ loss, Hes5 acting independently of Rbpjκ may maintain a subset of Arc progenitors that are proliferating and differentiating due to increased Mash1 activity, and the absence of Hes1 may also contribute to some progenitor cell death at E13.5. By contrast, conditional deletion of Rbpjκ from the telencephalon and subsequent loss of both Hes1 and Hes5 results in complete depletion of ventricular zone progenitors, coincident with a reduction in telencephalon size and accelerated neural commitment (Imayoshi et al, 2010). Therefore, our results suggest a novel Rbpjκ-independent role of Hes5 in maintaining the Arc progenitor population that is not observed in other brain regions.…”

Section: Discussioncontrasting

confidence: 53%

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

Aujla

Naratadam

et al. 2013

Development

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SUMMARYThe hypothalamic arcuate nucleus (Arc), containing pro-opoiomelanocortin (POMC), neuropeptide Y (NPY) and growth hormone releasing hormone (GHRH) neurons, regulates feeding, energy balance and body size. Dysregulation of this homeostatic mediator underlies diseases ranging from growth failure to obesity. Despite considerable investigation regarding the function of Arc neurons, mechanisms governing their development remain unclear. Notch signaling factors such as Hes1 and Mash1 are present in hypothalamic progenitors that give rise to Arc neurons. However, how Notch signaling controls these progenitor populations is unknown. To elucidate the role of Notch signaling in Arc development, we analyzed conditional loss-of-function mice lacking a necessary Notch co-factor, Rbpjκ, in Nkx2.1-cre-expressing cells (Rbpjκ cKO), as well as mice with expression of the constitutively active Notch1 intracellular domain (NICD) in Nkx2.1-cre-expressing cells (NICD Tg). We found that loss of Rbpjκ results in absence of Hes1 but not of Hes5 within the primordial Arc at E13.5. Additionally, Mash1 expression is increased, coincident with increased proliferation and accumulation of Arc neurons at E13.5. At E18.5, Rbpjκ cKO mice have few progenitors and show increased numbers of differentiated Pomc, NPY and Ghrh neurons. By contrast, NICD Tg mice have increased hypothalamic progenitors, show an absence of differentiated Arc neurons and aberrant glial differentiation at E18.5. Subsequently, both Rbpjκ cKO and NICD Tg mice have changes in growth and body size during postnatal development. Taken together, our results demonstrate that Notch/Rbpjκ signaling regulates the generation and differentiation of Arc neurons, which contribute to homeostatic regulation of body size. KEY WORDS: Arcuate, Notch, POMC, NPY, Hypothalamus, MouseNotch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons Paven K. Aujla, George T. Naratadam, Liwen Xu and Lori T. Raetzman* DEVELOPMENT 3512During embryonic development, cells migrate from the hypothalamic ventricular zone (HVZ) surrounding the ventral region of the third ventricle in order to form the Arc by E16.5 (Bayer and Altman, 1987;Ishii and Bouret, 2012;Shimada and Nakamura, 1973). One of the major functions of the Arc is to respond to food intake and energy expenditure. Energy-related hormone signals such as leptin are sensed by anorexic proopoiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART) neurons and orexic neuropeptide Y (NPY)/Agouti-related peptide (AgRP) neurons. POMC and NPY neurons regulate feeding behavior and are crucial to maintaining proper energy balance and homeostasis (Broberger, 2005;Morton et al., 2006;Srinivas et al., 2001). An additional subtype of neurons, growth hormone-releasing hormone (GHRH) neurons, are present in the Arc and regulate body size and growth by controlling release of growth hormone from the pituitary gland (Bouyer et al., 2007; Grossman et al., 1986).Despite the functional importance of ...

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Section: Discussioncontrasting

confidence: 53%

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

Aujla

Naratadam

et al. 2013

Development

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“…Using the Targetscan bioinformatics algorithm, we searched for direct targets of miR-146a with an emphasis on those genes that were shown to play a role in cancer stem cells, tumorigenesis or NSCs. Among several potential candidates, Notch1 is most prominent due to its established function in maintaining NSCs (23,27) (Fig. 5A).…”

Section: Egfr Activation and Pten Inactivation Synergistically Inducementioning

confidence: 99%

“…Upon binding to its ligand, Delta, the Notch intracellular domain (NICD; the activated form of Notch) is released from the membrane by presenilin/␥-secretase-mediated cleavage and translocates to the nucleus. In the nucleus, NICD forms a complex with Rbpj and activates the expression of several transcriptional repressors, such as Hes1 and Hes5, which inhibit neurogenesis (15,27,29). Thus, activation of the Notch pathway is essential to maintain both developing and adult NSCs (36).…”

mentioning

confidence: 99%

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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“…In the adult brain, the morphogenic proteins continue to subtly modulate the number and differentiation of neural precursor cells. In both the SGZ and the SVZ, Shh is essential for the maintenance of radial glia-like cells (Ahn and Joyner, 2005;Balordi and Fishell, 2007;Han et al, 2008), whereas Notch is fundamental for the neuronal differentiation of NSCs (Imayoshi et al, 2010;Pierfelice et al, 2011). Wnt can also promote the neuronal differentiation of NSCs in the SGZ (Lie et al, 2002), whereas BMP determines the glial fate of NSCs (Lim et al, 2000;Bonaguidi et al, 2005;Mira et al, 2010).…”

Section: Factors Regulating Nsc Differentiationmentioning

confidence: 99%

Neural stem cells: mechanisms and modeling

Yao

Gage

2012

Protein Cell

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In the adult brain, neural stem cells have been found in two major niches: the hippocampus and the olfactory bulb. Neurons derived from these stem cells contribute to learning, memory, and the autonomous repair of the brain under pathological conditions. Hence, the physiology of adult neural stem cells has become a significant component of research on synaptic plasticity and neuronal disorders. In addition, the recently developed induced pluripotent stem cell technique provides a powerful tool for researchers engaged in the pathological and pharmacological study of neuronal disorders. In this review, we briefly summarize the research progress in neural stem cells in the adult brain and in the neuropathological application of the induced pluripotent stem cell technique.

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Essential Roles of Notch Signaling in Maintenance of Neural Stem Cells in Developing and Adult Brains

Abstract: Activation of Notch signaling induces the expression of transcriptional repressor genes such as

Cited by 638 publications

References 58 publications

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Neural stem cells: mechanisms and modeling

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