Suppressor of fused controls perinatal expansion and quiescence of future dentate adult neural stem cells

Adult hippocampal neurogenesis requires the quiescent neural stem cell (NSC) pool to persist lifelong. However, establishment and maintenance of quiescent NSC pools during development is not understood. Here, we show that Suppressor of Fused (Sufu) controls establishment of the quiescent NSC pool during mouse dentate gyrus (DG) development by regulating Sonic Hedgehog (Shh) signaling activity. Deletion of Sufu in NSCs early in DG development decreases Shh signaling activity leading to reduced proliferation of NSCs, resulting in a small quiescent NSC pool in adult mice. We found that putative adult NSCs proliferate and increase their numbers in the first postnatal week and subsequently enter a quiescent state towards the end of the first postnatal week. In the absence of Sufu, postnatal expansion of NSCs is compromised, and NSCs prematurely become quiescent. Thus, Sufu is required for Shh signaling activity ensuring expansion and proper transition of NSC pools to quiescent states during DG development.

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Suppressor of Fused controls perinatal expansion and quiescence of future dentate adult neural stem cells

10.1101/454751 ◽

2018 ◽

Author(s):

Hirofumi Noguchi ◽

Jesse Garcia Castillo ◽

Kinichi Nakashima ◽

Samuel J. Pleasure

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Sonic Hedgehog ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Shh Signaling ◽

Suppressor Of Fused ◽

Adult Mice ◽

Adult Nscs ◽

Signaling Activity

AbstractAdult hippocampal neurogenesis requires the quiescent neural stem cell (NSC) pool to persist lifelong. The establishment and maintenance of quiescent NSC pools during development is not understood. Here we show that Suppressor of Fused (Sufu) controls establishment of the quiescent NSC pool during mouse dentate gyrus (DG) development through regulation of Sonic Hedgehog (Shh) signaling. Deletion of Sufuin NSCs at the beginning of DG development decreases Shh signaling leading to reduced proliferation of NSCs, resulting in a small quiescent NSC pool in adult mice. We found that putative adult NSCs proliferate and increase their numbers in the first postnatal week and subsequently become quiescent towards the end of the first postnatal week. In the absence of Sufu, postnatal expansion of NSCs is compromised, and NSCs prematurely become quiescent. Thus, Sufu is required for Shh signaling activity ensuring the expansion and proper transition of NSC pools to quiescence during DG development.

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Redox potential defines functional states of adult hippocampal stem cells

10.1101/606186 ◽

2019 ◽

Cited By ~ 2

Author(s):

Vijay S Adusumilli ◽

Tara L Walker ◽

Rupert W Overall ◽

Gesa M Klatt ◽

Salma A Zeidan ◽

...

Keyword(s):

Physical Activity ◽

Stem Cells ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

List Type ◽

Stem Cell Maintenance ◽

Adult Mice ◽

Intracellular Ros ◽

Functional States ◽

Marking Activity

SummaryIntracellular redox states regulate the balance between stem cell maintenance and activation. Increased levels of reactive oxygen species (ROS) are linked to proliferation and lineage specification. In contrast to this general principle, we show that in the hippocampus of adult mice it is the quiescent neural stem cells (NSCs) that maintain the highest ROS levels (hiROS). Classifying NSCs based on intracellular ROS content identified subpopulations with distinct molecular profiles, corresponding to functional states. Shifts in ROS content primed cells for a subsequent transition of cellular state, with lower cellular ROS content marking activity and differentiation. Physical activity, a known physiological activator of adult hippocampal neurogenesis, recruited the quiescent hiROS NSCs into proliferation via a transient Nox2-dependent ROS surge. In the absence of Nox2, baseline neurogenesis was unaffected, but the activity-induced increase in proliferation disappeared. These results describe a novel mechanism linking the modulation of cellular ROS by behavioral cues to the maintenance and activation of adult NSCs.HighlightsQuiescent adult hippocampal stem cells are characterized by high intracellular ROSChanges in intracellular ROS content precede changes in cellular stateAcute physical activity recruits quiescent cells into active proliferationThis recruitment is marked by a Nox2-dependent ROS spike in hiROS stem cells and represents an independent mode of cell cycle entryGraphical Abstract

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Brain Insulin-Like Growth Factor-I Directs the Transition from Stem Cells to Mature Neurons During Postnatal/Adult Hippocampal Neurogenesis

Stem Cells ◽

10.1002/stem.2397 ◽

2016 ◽

Vol 34 (8) ◽

pp. 2194-2209 ◽

Cited By ~ 21

Author(s):

Vanesa Nieto-Estévez ◽

Carlos O. Oueslati-Morales ◽

Lingling Li ◽

James Pickel ◽

Aixa V. Morales ◽

...

Keyword(s):

Stem Cells ◽

Growth Factor ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Insulin Like Growth Factor ◽

Factor I ◽

Brain Insulin ◽

Mature Neurons ◽

Growth Factor I

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Metabolic tuning of inhibition regulates hippocampal neurogenesis in the adult brain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2006138117 ◽

2020 ◽

Vol 117 (41) ◽

pp. 25818-25829

Author(s):

Xinxing Wang ◽

Hanxiao Liu ◽

Johannes Morstein ◽

Alexander J. E. Novak ◽

Dirk Trauner ◽

...

Keyword(s):

Dentate Gyrus ◽

Energy Homeostasis ◽

Inhibitory Neuron ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Neuron Activity ◽

Adult Mice ◽

Sphingosine 1 Phosphate ◽

Underlying Mechanisms

Hippocampus-engaged behaviors stimulate neurogenesis in the adult dentate gyrus by largely unknown means. To explore the underlying mechanisms, we used tetrode recording to analyze neuronal activity in the dentate gyrus of freely moving adult mice during hippocampus-engaged contextual exploration. We found that exploration induced an overall sustained increase in inhibitory neuron activity that was concomitant with decreased excitatory neuron activity. A mathematical model based on energy homeostasis in the dentate gyrus showed that enhanced inhibition and decreased excitation resulted in a similar increase in neurogenesis to that observed experimentally. To mechanistically investigate this sustained inhibitory regulation, we performed metabolomic and lipidomic profiling of the hippocampus during exploration. We found sustainably increased signaling of sphingosine-1-phosphate, a bioactive metabolite, during exploration. Furthermore, we found that sphingosine-1-phosphate signaling through its receptor 2 increased interneuron activity and thus mediated exploration-induced neurogenesis. Taken together, our findings point to a behavior-metabolism circuit pathway through which experience regulates adult hippocampal neurogenesis.

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Ghrelin gene products rescue cultured adult rat hippocampal neural stem cells from high glucose insult

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0096 ◽

2016 ◽

Vol 57 (3) ◽

pp. 171-184 ◽

Cited By ~ 3

Author(s):

Sehee Kim ◽

Chanyang Kim ◽

Seungjoon Park

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

High Glucose ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Gene Products ◽

Growth Hormone Secretagogue ◽

Phosphohistone H3 ◽

Ghrelin Gene ◽

Hippocampal Neural Stem Cells

Adult hippocampal neurogenesis is decreased in type 2 diabetes, and this impairment appears to be important in cognitive dysfunction. Previous studies suggest that ghrelin gene products (acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (OB)) promote neurogenesis. Therefore, we hypothesize that ghrelin gene products may reduce the harmful effects of high glucose (HG) on hippocampal neural stem cells (NSCs). The aim of this study was to investigate the role of these peptides on the survival of cultured hippocampal NSCs exposed to HG insult. Treatment of hippocampal NSCs with AG, UAG or OB inhibited HG-induced cell death and apoptosis. Exposure of cells to the growth hormone secretagogue receptor 1a antagonist abolished the protective effects of AG against HG toxicity, whereas those of UAG or OB were preserved. All three peptides attenuated HG-induced decrease in BrdU-labeled and phosphohistone-H3-labeled cells. We also investigated the effects of ghrelin gene products on the regulation of apoptosis at the mitochondrial level. AG, UAG or OB rescued hippocampal NSCs from HG insult by inhibiting intracellular and mitochondrial reactive oxygen species generation and stabilizing mitochondrial transmembrane potential. In addition, cells treated with ghrelin gene products showed an increased Bcl-2 and decreased Bax levels, thereby increasing the Bcl-2/Bax ratio, inhibiting cytochrome c release and preventing caspase-3 activation. Finally, AG-, UAG- or OB-mediated protection was dependent on the activities of adenosine monophosphate-activated protein kinase/uncoupling protein 2 pathway. Our data indicate that ghrelin gene products may act as survival factors that preserve mitochondrial function and inhibit oxidative stress-induced apoptosis.

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α2-Chimaerin is essential for neural stem cell homeostasis in mouse adult neurogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903891116 ◽

2019 ◽

Vol 116 (27) ◽

pp. 13651-13660 ◽

Cited By ~ 1

Author(s):

Yi-Ting Su ◽

Shun-Fat Lau ◽

Jacque P. K. Ip ◽

Kit Cheung ◽

Tom H. T. Cheung ◽

...

Keyword(s):

Stem Cell ◽

Neural Stem Cell ◽

Rho Gtpase ◽

Hippocampal Neurogenesis ◽

Conditional Knockout ◽

Adult Hippocampal Neurogenesis ◽

Adult Neural Stem Cell ◽

Conditional Deletion ◽

Adult Nscs ◽

Anxiety Depression

Adult hippocampal neurogenesis involves the lifelong generation of neurons. The process depends on the homeostasis of the production of neurons and maintenance of the adult neural stem cell (NSC) pool. Here, we report that α2-chimaerin, a Rho GTPase-activating protein, is essential for NSC homeostasis in adult hippocampal neurogenesis. Conditional deletion of α2-chimaerin in adult NSCs resulted in the premature differentiation of NSCs into intermediate progenitor cells (IPCs), which ultimately depleted the NSC pool and impaired neuron generation. Single-cell RNA sequencing and pseudotime analyses revealed that α2-chimaerin–conditional knockout (α2-CKO) mice lacked a unique NSC subpopulation, termed Klotho-expressing NSCs, during the transition of NSCs to IPCs. Furthermore, α2-CKO led to defects in hippocampal synaptic plasticity and anxiety/depression-like behaviors in mice. Our findings collectively demonstrate that α2-chimaerin plays an essential role in adult hippocampal NSC homeostasis to maintain proper brain function.

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Sonic Hedgehog Signaling Mediates Resveratrol to Increase Proliferation of Neural Stem Cells After Oxygen-Glucose Deprivation/Reoxygenation Injury in Vitro

Cellular Physiology and Biochemistry ◽

10.1159/000374009 ◽

2015 ◽

Vol 35 (5) ◽

pp. 2019-2032 ◽

Cited By ~ 21

Author(s):

Wei Cheng ◽

Pingping Yu ◽

Li Wang ◽

Changbo Shen ◽

Xiaosong Song ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Sonic Hedgehog ◽

Glucose Deprivation ◽

Adult Brain ◽

Immunocytochemical Staining ◽

Oxygen Glucose Deprivation ◽

Shh Signaling ◽

Gli 1

Background/Aims: There is interest in drugs and rehabilitation methods to enhance neurogenesis and improve neurological function after brain injury or degeneration. Resveratrol may enhance hippocampal neurogenesis and improve hippocampal atrophy in chronic fatigue mice and prenatally stressed rats. However, its effect and mechanism of neurogenesis after stroke is less well understood. Sonic hedgehog (Shh) signaling is crucial for neurogenesis in the embryonic and adult brain, but relatively little is known about the role of Shh signaling in resveratrol-enhanced neurogenesis after stroke. Methods: Neural stem cells (NSCs) before oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro were pretreated with resveratrol with or without cyclopamine. Survival and proliferation of NSCs was assessed by the CCK8 assay and BrdU immunocytochemical staining. The expressions and activity of signaling proteins and mRNAs were detected by immunocytochemistry, Western blotting, and RT-PCR analysis. Results: Resveratrol significantly increased NSCs survival and proliferation in a concentration-dependent manner after OGD/R injury in vitro. At the same time, the expression of Patched-1, Smoothened (Smo), and Gli-1 proteins and mRNAs was upregulated, and Gli-1 entered the nucleus, which was inhibited by cyclopamine, a Smo inhibitor. Conclusion: Shh signaling mediates resveratrol to increase NSCs proliferation after OGD/R injury in vitro.

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Sulforaphane Inhibits Self-renewal of Lung Cancer Stem Cells Through the Modulation of Polyhomeotic Homolog 3 and Sonic Hedgehog Signaling Pathways

10.21203/rs.2.11459/v1 ◽

2019 ◽

Author(s):

FanPing Wang ◽

Jiateng Zhong ◽

Shanshan Wang ◽

Caijuan Qiao ◽

Xiangyang Li ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Western Blot ◽

Cancer Cells ◽

Signaling Pathways ◽

Sonic Hedgehog ◽

Self Renewal ◽

Shh Signaling ◽

Lung Cancer Stem Cells

Abstract Background: Sulforaphane (SFN), an active compound in cruciferous vegetables has been characterized for its antiproliferative capacity. We investigated the role and molecular mechanism through which SFN regulates proliferation and self-renewal of lung cancer stem cells. Methods: Lung cancer stem cells (CD133-positive cells) were isolated by MACs and then measured by flow cytometry. The ability of cell proliferation was assessed by MTT assays and tumorsphere formation assays. The expressions of Sonic Hedgehog (Shh), Smoothened (Smo), Gli1 and Human Polyhomeotic Homolog 3 (PHC3) in cells were measured by quantitative reverse transcription polymerase chain reaction (qPCR) and western blot assays. The expression of transcription factor SOX2 in lung cancer stem cells was also determined by western blot assay. Shh was knocked down by siRNA to further study the role of SFN and Shh signaling pathways in lung cancer. Results: SFN inhibited the proliferation of lung cancer cells and lung cancer stem cells simultaneously. Meanwhile, we observed that Sonic Hedgehog (SHH) signaling pathway, SOX2 and Polyhomeotic Homolog 3 (PHC3) were highly activated in lung cancer stem cells. Knock-down of Shh led to reduced H460 and A549 cells proliferation. Furthermore, we observed that SFN inhibited the activity of PHC3 and SHH signaling pathways in the lung cancer stem cells. In addition, SFN combined with Knock-down of Shh gene showed a greater effect on the proliferation of lung cancer cells. Conclusion: SFN is an effective new drug which can inhibit proliferation of lung cancer stem cells through the modulation of PHC3 and SHH signaling pathways. It provides a novel target for improving therapeutic efficacy for lung cancer stem cells.

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