Loss of GSK-3 Causes Abnormal Astrogenesis and Behavior in Mice

Jung, Eui‐Man; Ka, Minhan; Kim, Woo Yang

doi:10.1007/s12035-015-9326-8

Cited by 41 publications

(40 citation statements)

References 68 publications

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“…68,69 In both studies, mice survived and there were no reported reductions in lifespan. Kim et al, 68 investigated the consequences of combined GSK-3α and GSK-3β deletion in neural progenitor cells.…”

Section: Discussionmentioning

confidence: 91%

“…These mice showed massive increases in neural progenitor cell proliferation without enhanced apoptosis when compared to controls. Jung et al, 69 generated a conditional knockout mouse, in which GSK-3α and GSK-3β were deleted in astrocytes. Astrocyte specific GSK-3-DKO mice exhibited anxiety and altered social behavior with no effect on the lifespan.…”

Section: Discussionmentioning

confidence: 99%

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Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy

Zhou

Ahmad

Parikh

et al. 2016

Circulation Research

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Rationale Cardiac myocyte-specific deletion of either Glycogen Synthase Kinase (GSK)3A or GSK3B leads to cardiac protection following myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration due to the fact that all GSK-3–targeted drugs including the drugs already in clinical trial target both isoforms of GSK-3 and none are isoform specific. Objective To identify the consequences of combined deletion of cardiac myocyte GSK3A and GSK3B in heart function. Methods and Results We generated tamoxifen-inducible cardiac myocyte-specific mice lacking both GSK-3 isoforms (double knockout, DKO). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, DKO hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from DKO implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. DKO cardiac myocytes showed cell cycle progression resulting in increased DNA content and multi-nucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes. Conclusion Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis and its loss is incompatible with life due to cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy

Zhou

Ahmad

Parikh

et al. 2016

Circulation Research

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“…64, 65 DNA constructs were transfected into attached cells using lipofectamine (Thermo Fisher Scientific Inc., Waltham, MA, USA) according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Transactivation of TrkB by Sigma-1 receptor mediates cocaine-induced changes in dendritic spine density and morphology in hippocampal and cortical neurons

Kook

Liao

et al. 2016

Cell Death Dis

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Cocaine is a highly addictive narcotic associated with dendritic spine plasticity in the striatum. However, it remains elusive whether cocaine modifies spines in a cell type-specific or region-specific manner or whether it alters different types of synapses in the brain. In addition, there is a paucity of data on the regulatory mechanism(s) involved in cocaine-induced modification of spine density. In the current study, we report that cocaine exposure differentially alters spine density, spine morphology, and the types of synapses in hippocampal and cortical neurons. Cocaine exposure in the hippocampus resulted in increased spine density, but had no significant effect on cortical neurons. Although cocaine exposure altered spine morphology in both cell types, the patterns of spine morphology were distinct for each cell type. Furthermore, we observed that cocaine selectively affects the density of excitatory synapses. Intriguingly, in hippocampal neurons cocaine-mediated effects on spine density and morphology involved sigma-1 receptor (Sig-1 R) and its downstream TrkB signaling, which were not the case in cortical neurons. Furthermore, pharmacological inhibition of Sig-1 R prevented cocaine-induced TrkB activation in hippocampal neurons. Our findings reveal a novel mechanism by which cocaine induces selective changes in spine morphology, spine density, and synapse formation, and could provide insights into the cellular basis for the cognitive impairment observed in cocaine addicts.

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“…Stereological analysis of immunostained cells was performed by analyzing 1-in-6 series of 40mm coronal sections (240-mm apart). 55 The LC3 puncta numbers were assessed using ImageJ software (NIH). Immunostained sections were imaged by confocal microscopy with a 40X objective.…”

Section: Morphometrymentioning

confidence: 99%

“…BrdU injection and cell cycle analysis were performed as described previously. 55,56 Intraperitoneal injection of BrdU (20mg per kg body weight) was performed into pregnant mice at E13.5-15.5. For the analysis of cell cycle re-entry, BrdU was administered to control (Mtor loxP/C ; Dlx5/6-CIE or Mtor loxP/C ; Nkx2-1-Cre) and knockout (mtor loxP/loxP ; Dlx5/6-CIE or mtor-loxP/loxP ; Nkx2.1-Cre) mice for 24 h. Brains were fixed with 4% paraformaldehyde, sliced, and immunostained with antibodies to BrdU and MKI67.…”

Section: Brdu Administration and Cell Cycle Analysismentioning

confidence: 99%

MTOR controls genesis and autophagy of GABAergic interneurons during brain development

Smith

Kim

2017

Autophagy

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Interneuron progenitors in the ganglionic eminence of the ventral telencephalon generate most cortical interneurons during brain development. However, the regulatory mechanism of interneuron progenitors remains poorly understood. Here, we show that MTOR (mechanistic target of rapamycin [serine/threonine kinase]) regulates proliferation and macroautophagy/autophagy of interneuron progenitors in the developing ventral telencephalon. To investigate the role of MTOR in interneuron progenitors, we conditionally deleted the Mtor gene in mouse interneuron progenitors and their progeny by using Tg(mI56i-cre,EGFP)1Kc/Dlx5/6-Cre-IRES-EGFP and Nkx2-1-Cre drivers. We found that Mtor deletion markedly reduced the number of interneurons in the cerebral cortex. However, relative positioning of cortical interneurons was normal, suggesting that disruption of progenitor self-renewal caused the decreased number of cortical interneurons in the Mtor-deleted brain. Indeed, Mtor-deleted interneuron progenitors showed abnormal proliferation and cell cycle progression. Additionally, we detected a significant activation of autophagy in Mtor-deleted brain. Our findings suggest that MTOR plays a critical role in the regulation of cortical interneuron number and autophagy in the developing brain.

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Loss of GSK-3 Causes Abnormal Astrogenesis and Behavior in Mice

Cited by 41 publications

References 68 publications

Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy

Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy

Transactivation of TrkB by Sigma-1 receptor mediates cocaine-induced changes in dendritic spine density and morphology in hippocampal and cortical neurons

MTOR controls genesis and autophagy of GABAergic interneurons during brain development

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