Comparative analysis of CNS populations in knockout mice with altered growth hormone responsiveness

Ransome, Mark I.; Goldshmit, Yona; Bartlett, Perry F.; Waters, Michael J.; Turnley, Ann M.

doi:10.1111/j.0953-816x.2004.03308.x

Cited by 73 publications

(58 citation statements)

References 51 publications

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“…8,11,12,36,37 In regard to the findings with GH, our data agree with a previous report demonstrating reduced brain size and sparser dendritic arborization in GH receptor-deficient (GHR À/À ) mice. 38 Neurite initiation and sprouting were significantly increased in Stat5 À/À neurons as compared to Stat5 þ / þ cells, suggesting that Stat5 activity might negatively regulate neurite outgrowth. Therefore, we cannot exclude the possibility that the increased baseline of sprouting in Stat5 À/À neurons might have masked the stimulatory effects of EPO and GH.…”

Section: Discussionmentioning

confidence: 96%

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

et al. 2008

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The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) are activated by the neuroprotective and neurotrophic cytokines, erythropoietin (EPO) and growth hormone (GH). Here, we show a dissociation of the intracellular pathway mediating the protective effect of EPO against glutamate toxicity from that needed for its neurotrophic activity using hippocampal neuronal cultures from Stat5a/b-knockout (Stat5 À/À ) mouse fetuses. Both pretreatment and post-treatment with EPO counteracted glutamate-induced cell death in Stat5 þ / þ and Stat5 À/À neurons. Acute pharmacological inhibition of Janus kinase 2 (JAK2)/Stat signalling had no effect on EPO neuroprotection, whereas inhibition of phosphatidylinositol-3 0 kinase (PI3K)/Akt pathway abolished the protective effect of EPO in both Stat5 þ / þ and Stat5 À/À neurons. GH effectively protected Stat5 þ / þ cells against glutamate toxicity but had no effect in Stat5 À/À neurons or in Stat5 þ / þ neurons treated with JAK2/Stat or PI3K inhibitor. EPO and GH stimulated neurite outgrowth and branching of Stat5 þ / þ neurons by activating PI3K/Akt signalling but had no trophic effect in Stat5 À/À cells. We conclude that in hippocampal neurons, Stat5 is not required for neuroprotection by EPO but is together with Akt essential for its neurotrophic activity. Both Stat5 and Akt are needed for neuroprotective and neurotrophic signalling of GH in neurons. The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) control cell fate decisions such as differentiation, proliferation and apoptosis. 1 Stat5 mediates cellular response to cytokines, growth factors and hormones. 1 Upon binding to their membrane receptors, growth factors such as erythropoietin (EPO) and growth hormone (GH) activate Janus kinase 2 (JAK2), causing activation of Stat5 by its phosphorylation, dimerization and translocation to the nucleus, where Stat5 induces expression of various antiapoptotic genes. 1 Indicative of an impaired functioning of EPO and GH receptor-associated signalling, Stat5a/b-knockout mice (Stat5 À/À ) are severely anaemic and growth retarded and the vast majority die perinatally. 2 Stat5 is expressed in the developing nervous system. 3,4 Recent studies suggest a role for Stat5 in neuronal migration and axon guidance in the developing brain 3 and a novel therapeutic potential for constitutively active Stat5 in reducing axonal outgrowth defects in spinal muscular atrophy-like motor neurons. 5 Since activation of Stat5 in neurons accompanies the antiapoptotic and neuroprotective effects of EPO in vitro and in vivo, 6-12 Stat5 has been suggested to mediate the protective effects of EPO in neuronal cells. Nevertheless, the molecular mechanisms of EPO receptor (EPOR) activation in neurons are complex, as multiple neuroprotective signalling pathways are activated downstream of EPOR/JAK2. In addition to Stat5, best characterized from these are the phosphatidylinositol-3 0 kinase (PI3K)/ Akt, nuclear factor-kB and Ras/mitogen-activated p...

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Section: Discussionmentioning

confidence: 96%

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

et al. 2008

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“…In addition, SOCS2 plays a role in the nervous system [20][21][22] and the immune response [23] and might participate in certain cancers [24][25][26]. To date, little is known about the impact of SOCS2 on pancreatic physiology.…”

Section: Introductionmentioning

confidence: 99%

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

et al. 2010

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Aims/hypothesis Suppressor of cytokine signalling (SOCS) proteins are powerful inhibitors of pathways involved in survival and function of pancreatic beta cells. Whereas SOCS1 and SOCS3 have been involved in immune and inflammatory processes, respectively, in beta cells, nothing is known about SOCS2 implication in the pancreas. Methods Transgenic (tg) mice were generated that constitutively produced SOCS2 in beta cells (βSOCS2) to define whether this protein is implicated in beta cell functioning and/or survival.Results Constitutive production of SOCS2 in beta cells leads to hyperglycaemia and glucose intolerance. This phenotype is not a consequence of decreased beta cell mass or inhibition of insulin synthesis. However, insulin secretion to various secretagogues is profoundly altered in intact animals and isolated islets. Interestingly, constitutive SOCS2 production dampens the rise in cytosolic free calcium concentration induced by glucose, while glucose metabolism is unchanged. Moreover, tg islets have a depletion in endoplasmic reticulum Ca 2+ stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, inElectronic supplementary material The online version of this article

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“…Although our investigation was targeting adult effects of local GH, it has to be kept in mind that the bGH-Tg came into effect in the early postnatal life when GFAP started to become expressed. As previous TG models that either increase or decrease GH signalling affect astrocyte numbers (Turnley et al 2002, Ransome et al 2004, at least in the cerebral cortex, it is plausible that astrocyte numbers may have slowly accumulated during the development. Such a slow accumulation may not have been detected in our assays of proliferating cells.…”

Section: Discussionmentioning

confidence: 90%

“…Two previous studies using TG models affecting GH signalling in the developing and adult brain have demonstrated an influence on the number of astrocytes in the cerebral cortex (Turnley et al 2002, Ransome et al 2004. Specifically, disruption of GH signalling, via GH receptor (GHR K/K ), decreased astrocyte numbers and increased neuron numbers (Ransome et al 2004), while increasing GH signalling via disrupting the suppressor of cytokine signalling 2 (SOCS2) decreased neuron numbers and presumably increased astrocyte numbers (Turnley et al 2002). Neither from these studies nor from our previous studies using glial fibrillary acidic protein (GFAP)-induced bGH-Tg, is it known whether hippocampal function is affected, as hippocampus-related parameters were not investigated.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, brain-specific bGH overexpression increases body weight and alters (mostly negatively) several cardiac measures of function (Bohlooly-Y et al 2005a), as well as increases eating behaviour (Bohlooly-Y et al 2005b). Two previous studies using TG models affecting GH signalling in the developing and adult brain have demonstrated an influence on the number of astrocytes in the cerebral cortex (Turnley et al 2002, Ransome et al 2004. Specifically, disruption of GH signalling, via GH receptor (GHR K/K ), decreased astrocyte numbers and increased neuron numbers (Ransome et al 2004), while increasing GH signalling via disrupting the suppressor of cytokine signalling 2 (SOCS2) decreased neuron numbers and presumably increased astrocyte numbers (Turnley et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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Local overexpression of GH and GH/IGF1 effects in the adult mouse hippocampus

Walser¹,

Samà²,

Wickelgren³

et al. 2012

Journal of Endocrinology

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GH therapy improves hippocampal functions mainly via circulating IGF1. However, the roles of local GH and IGF1 expression are not well understood. We investigated whether transgenic (TG) overexpression in the adult brain of bovine GH (bGH) under the control of the glial fibrillary acidic protein (GFAP) promoter affected cellular proliferation and the expression of transcripts known to be induced by systemic GH in the hippocampus. Cellular proliferation was examined by 5-bromo-2 0 -deoxyuridine immunohistochemistry. Quantitative PCR and western blots were performed. Although robustly expressed, bGH-Tg did not increase either cell proliferation or survival. However, bGH-Tg modestly increased Igf1 and Gfap mRNAs, whereas other GH-associated transcripts were unaffected, i.e. the GH receptor (Ghr), IGF1 receptor (Igf1r), 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase (Cnp), ionotropic glutamate receptor 2a (Nr2a (Grin2a)), opioid receptor delta (Dor), synapse-associated protein 90/postsynaptic density-95-associated protein (Sapap2 (Dlgap2)), haemoglobin beta (Hbb) and glutamine synthetase (Gs (Glul )). However, IGF1R was correlated with the expression of Dor, Nr2a, Sapap2, Gs and Gfap. In summary, although local bGH expression was robust, it activated local IGF1 very modestly, which is probably the reason for the low response of previous GH-associated response parameters. This would, in turn, indicate that hippocampal GH is less important than endocrine GH. However, as most transcripts were correlated with the expression of IGF1R, there is still a possibility for endogenous circulating or local GH to act via IGF1R signalling. Possible reasons for the relative bio-inactivity of bGH include the bell-shaped dose-response curve and cell-specific expression of bGH.

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Comparative analysis of CNS populations in knockout mice with altered growth hormone responsiveness

Cited by 73 publications

References 51 publications

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

Local overexpression of GH and GH/IGF1 effects in the adult mouse hippocampus

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