Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells

Fernando, Ruani; Eleuteri, Boris; Abdelhady, Shaimaa; Nussenzweig, André; Andäng, Michael; Ernfors, Patrik

doi:10.1073/pnas.1014993108

Cited by 134 publications

(124 citation statements)

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“…We propose that physiological levels of GABA synthesized by SSCs or interstitial cells through GABA A receptors result in a decreased proliferation of SSCs. GABA control over proliferation is also found in ES cells and adult neural stem cells, even in tumors where putative cancer stem cells reside, suggesting a developmentally conserved role of GABA as a negative regulator of stem cell proliferation [19,20,38]. In conclusion, our study provides direct evidence that the GABA system is present in mouse SSCs, and indicates that GABA inhibits SSC proliferation independently of apoptosis in vitro.…”

Section: Discussionmentioning

confidence: 52%

“…The inhibitory effect of GABA on cell proliferation is not restricted to the nervous system. GABA has recently been shown to limit the proliferation of pluripotent embryonic stem cells and adult neural stem cells [19,20]. In light of these recent findings, we investigated whether GABA is present in SSCs and if it influences their proliferation.…”

Section: Introductionmentioning

confidence: 99%

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GABA exists as a negative regulator of cell proliferation in spermaogonial stem cells

Zheng

et al. 2013

Cellular and Molecular Biology Letters

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γ-amino butyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian central nervous system. GABA is also found in many peripheral tissues, where it has important functions during development. Here, we identified the existence of the GABA system in spermatogonial stem cells (SSCs) and found that GABA negatively regulates SSC proliferation. First, we demonstrated that GABA and its synthesizing enzymes were abundant in the testes 6 days postpartum (dpp), suggesting that GABA signaling regulates SSCs function in vivo. In order to directly examine the effect of GABA on SSC proliferation, we then established an in vitro culture system for long-term expansion of SSCs. We showed that GABA A receptor subunits, including α1, α5, β1, β2, β3 and γ3, the synthesizing enzyme GAD67, and the transporter GAT-1, are expressed in SSCs. Using phosphorylated histone H3 (pH3) staining, we demonstrated that GABA or the GABA A R-specific agonist muscimol reduced the proliferation of SSCs. This GABA regulation of SSC proliferation was shown to be independent of apoptosis using the TUNEL assay. These results suggest that GABA acts as a negative regulator of SSC proliferation to maintain the homeostasis of spermatogenesis in the testes.

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

GABA exists as a negative regulator of cell proliferation in spermaogonial stem cells

Zheng

et al. 2013

Cellular and Molecular Biology Letters

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“…In the brain, this niche provides the appropriate environment for stem and progenitor cells, including RGLs, and niche signals are crucial in adult neurogenesis (Ming and Song, 2011). Work from several laboratories during the past decade has revealed that neurotransmitters provide important components of the niche signals and influence several aspects of neurogenesis, both during normal physiological conditions and in disease models (discussed further below) (Höglinger et al, 2004;Liu et al, 2005;Berg et al, 2011;Fernando et al, 2011;Alfonso et al, 2012). …”

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confidence: 99%

Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain

et al. 2013

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SummaryIt was long thought that no new neurons are added to the adult brain. Similarly, neurotransmitter signaling was primarily associated with communication between differentiated neurons. Both of these ideas have been challenged, and a crosstalk between neurogenesis and neurotransmitter signaling is beginning to emerge. In this Review, we discuss neurotransmitter signaling as it functions at the intersection of stem cell research and regenerative medicine, exploring how it may regulate the formation of new functional neurons and outlining interactions with other signaling pathways. We consider evolutionary and cross-species comparative aspects, and integrate available results in the context of normal physiological versus pathological conditions. We also discuss the potential role of neurotransmitters in brain size regulation and implications for cell replacement therapies. Key words: Adult neurogenesis, Homeostasis, Neural stem cell, Neurotransmitter, Regeneration IntroductionIn the brain, signaling via neurotransmitters, small molecules released by neurons to communicate with other cells, has primarily been associated with the function rather than with the formation of neurons. However, several reports have identified roles for neurotransmitters in cell fate determination in a wide range of species both within and outside the central nervous system (CNS). A thorough discussion on the evolutionary origin of neurotransmitter signaling is outside the scope of this Review, but it is important to note that both neurotransmitters and their receptors (see Table 1) are present and functionally important in organisms without a nervous system. For example, γ-aminobutyric acid (GABA), glutamate and nitric oxide (NO) have all been detected in sponges and shown to regulate cell behavior (Ellwanger et al., 2007;Elliott and Leys, 2010). A recent transcriptome profiling of the sponge A. queenslandica revealed the expression of wide repertoire of components active in synapses found in the vertebrate nervous systems (Conaco et al., 2012). In the social amoeba Dictysotelium, disruption of a glutamate receptor by homologous recombination reveals a role for glutamate signaling in the suppression of cell division (Taniura et al., 2006), while GABA induces terminal differentiation of spores through a GABA B receptor (Anjard and Loomis, 2006). GABA and glutamate appear to play opposing roles in spore induction (Fountain, 2010) in Dictyostelium, indicating that the apparent antagonistic relationship between glutamate and GABA signaling was established prior to the evolution of synaptic communication in the CNS.Furthermore, neurotransmitters control cell proliferation during development long before the onset of neurogenesis in mammals, as exemplified by GABA signaling in the early embryo (Andäng et al., 2008). Once developmental neurogenesis is initiated, neurotransmitter signaling has an impact on several aspects of neurogenesis, including proliferation, migration and differentiation in various locations in the CNS, such as the tele...

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“…H2AX is required for cell cycle arrest and DNA repair following doublestranded DNA breaks [38,39] . DNA damage results in the rapid phosphorylation of H2AX by ATM [38,40] . Within minutes of DNA damage, H2AX is phosphorylated at the sites of the DNA damage [38] .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the ATM/H2AX signaling pathway is important in the response to and repair of DNA damage induced by OS [38,41] . Our results with ATM and H2AX clearly showed that OS after liver surgery caused DNA damage signaling and triggered subsequent DNA repair.…”

mentioning

confidence: 99%

Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

Hori¹,

Üemoto²,

Chen³

et al. 2014

WJH

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AIM:To investigate oxidative stress (OS)-mediated damage and the behavior of extracellular matrices in various rat models because shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery. These injuries also cause fatal liver damage. METHODS:Rats were divided into four groups according to the surgery performed: control; hepatectomy with 40% liver remnant (60% hepatectomy); orthotopic liver transplantation (OLT) with whole liver graft (100% OLT); and split OLT (SOLT) with 40% graft (40% SOLT). Survival was evaluated. Blood and liver samples were collected at 6 h after surgery. Biochemical and histopathological examinations were performed. OSinduced damage, 4-hydroxynonenal, ataxia-telangiectasia mutated kinase, histone H2AX, phosphatidylinositol 3-kinase (PI3K) and Akt were evaluated by western blotting. Behavior of extracellular matrices, matrix metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were also evaluated by western blotting and zymography. RESULTS:Although 100% OLT survived, 60% hepatectomy and 40% SOLT showed poor survival. Histopathological, immunohistological, biochemical and protein assays revealed that 60% hepatectomy, 100% OLT and 40% SOLT showed liver damage. PI3K and Akt were decreased in 60% hepatectomy and 40% SOLT. For protein expression, 40% SOLT showed differences in MMP-9, MMP-2 and TIMP-2. TIMP-1 showed differences in 60% hepatectomy and 40% SOLT. For protein activity, MMP-9 demonstrated significant differences in 60% hepatectomy, 100% OLT and 40% SOLT. CONCLUSION: Under conditions with an insufficient liver remnant, prevention of OS-induced damage viathe Akt/PI3K pathway may be key to improve the postoperative course. MMP-9 may be also a therapeutic target after surgery. Hori T et al . Hepatic damage after liver surgeryCore tip: Although shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery, these injuries also cause fatal liver damage. Postoperative liver damage is still a critical matter in the field of liver surgery. Oxidative stress and extracellular matrices are important for liver regeneration after surgery and these may be important keys to overcome current problems in the field of liver surgery. Here, we investigated oxidative stress-mediated damage and the behavior of extracellular matrices in various rat models with liver surgery.Hori T, Uemoto S, Chen F, Gardner LB, Baine AMT, Hata T, Kogure T, Nguyen JH. ��idative stress and e�tracellular ma��idative stress and e�tracellular matrices after hepatectomy and liver transplantation in rats. World

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Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells

Cited by 134 publications

References 44 publications

GABA exists as a negative regulator of cell proliferation in spermaogonial stem cells

GABA exists as a negative regulator of cell proliferation in spermaogonial stem cells

Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain

Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

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