scholarly journals Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide

2016 ◽  
Vol 212 (5) ◽  
pp. 545-560 ◽  
Author(s):  
Chenran Wang ◽  
Song Chen ◽  
Syn Yeo ◽  
Gizem Karsli-Uzunbas ◽  
Eileen White ◽  
...  
Keyword(s):  
Stem Cells ◽  
Superoxide Dismutase ◽  
Neural Stem Cells ◽  
Knockout Mice ◽  
Critical Role ◽  
Conditional Knockout ◽  
Biological Processes ◽  
Aggregate Formation ◽  
Conditional Knockout Mice

Autophagy plays important roles in many biological processes, but our understanding of the mechanisms regulating stem cells by autophagy is limited. Interpretations of earlier studies of autophagy using knockouts of single genes are confounded by accumulating evidence for other functions of many autophagy genes. Here, we show that, in contrast to Fip200 deletion, inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 does not impair the maintenance and differentiation of postnatal neural stem cells (NSCs). Only Fip200 deletion, but not Atg5, Atg16L1, or Atg7 deletion, caused p62/sequestome1 aggregates to accumulate in NSCs. Fip200 and p62 double conditional knockout mice demonstrated that p62 aggregate formation triggers aberrant superoxide increases by impairing superoxide dismutase functions. By comparing the inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 with Fip200 deletion, we revealed a critical role of increased p62 in determining the fate of autophagy-deficient NSCs through intracellular superoxide control.

Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice

2019 ◽  
Vol 29 (5) ◽  
pp. 727-735 ◽  
Author(s):  
Yuhang Cao ◽  
Yingliang Zhuang ◽  
Junchen Chen ◽  
Weize Xu ◽  
Yikai Shou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Neuronal Development ◽  
Conditional Knockout ◽  
Biological Processes ◽  
Adult Neural Stem Cells ◽  
Proliferation And Differentiation

Abstract N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.

scholarly journals Critical Role of PI3K/Akt/GSK3β in Motoneuron Specification from Human Neural Stem Cells in Response to FGF2 and EGF

PLoS ONE ◽  
2011 ◽  
Vol 6 (8) ◽  
pp. e23414 ◽  
Author(s):  
Luis Ojeda ◽  
Junling Gao ◽  
Kristopher G. Hooten ◽  
Enyin Wang ◽  
Jason R. Thonhoff ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Critical Role ◽  
Human Neural Stem Cells

scholarly journals Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice

2002 ◽  
Vol 99 (13) ◽  
pp. 8938-8943 ◽  
Author(s):  
A. Sainsbury ◽  
C. Schwarzer ◽  
M. Couzens ◽  
S. Fetissov ◽  
S. Furtinger ◽  
...  
Keyword(s):  
Body Weight ◽  
Knockout Mice ◽  
Conditional Knockout ◽  
Weight Regulation ◽  
Body Weight Regulation ◽  
Conditional Knockout Mice

A facile one-step strategy for the generation of conditional knockout mice to explore the role of Notch1 in oroesophageal tumorigenesis

2016 ◽  
Vol 469 (3) ◽  
pp. 761-767 ◽  
Author(s):  
Masita Mandasari ◽  
Wanlada Sawangarun ◽  
Ken-ichi Katsube ◽  
Kou Kayamori ◽  
Akira Yamaguchi ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Conditional Knockout ◽  
Conditional Knockout Mice ◽  
One Step

scholarly journals Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells

2008 ◽  
Vol 181 (7) ◽  
pp. 1065-1072 ◽  
Author(s):  
Daisuke Hashimoto ◽  
Masaki Ohmuraya ◽  
Masahiko Hirota ◽  
Akitsugu Yamamoto ◽  
Koichi Suyama ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Knockout Mice ◽  
Early Stage ◽  
Acinar Cells ◽  
Conditional Knockout ◽  
Pancreatic Acinar Cells ◽  
Trypsinogen Activation ◽  
Conditional Knockout Mice ◽  
Cellular Environment

Autophagy is mostly a nonselective bulk degradation system within cells. Recent reports indicate that autophagy can act both as a protector and killer of the cell depending on the stage of the disease or the surrounding cellular environment (for review see Cuervo, A.M. 2004. Trends Cell Biol. 14:70–77). We found that cytoplasmic vacuoles induced in pancreatic acinar cells by experimental pancreatitis were autophagic in origin, as demonstrated by microtubule-associated protein 1 light chain 3 expression and electron microscopy experiments. To analyze the role of macroautophagy in acute pancreatitis, we produced conditional knockout mice lacking the autophagy-related 5 gene in acinar cells. Acute pancreatitis was not observed, except for very mild edema in a restricted area, in conditional knockout mice. Unexpectedly, trypsinogen activation was greatly reduced in the absence of autophagy. These results suggest that autophagy exerts devastating effects in pancreatic acinar cells by activation of trypsinogen to trypsin in the early stage of acute pancreatitis through delivering trypsinogen to the lysosome.

Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 318-324 ◽  
Author(s):  
Lei Yang ◽  
Shuoji Zhu ◽  
Yongqing Li ◽  
Jian Zhuang ◽  
Jimei Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Heart Function ◽  
Critical Role ◽  
Human Umbilical Cord ◽  
Stem Cell Markers ◽  
Quantitative Real Time Pcr ◽  
Qrt Pcr

Background: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. Objective: To investigate the role of pygo2 in the differentiation of hUC-MSCs into cardiomyocytes. Methods: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p− group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes—including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin—were analyzed by qRT-PCR following transfection with the virus at one, two and three weeks. Results : After three days of incubation, there were no significant changes in the expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1, P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P < 0.01, SOX2: 0.209 ± 0.109 VS 1, P < 0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, were increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p− group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUCMSCs gradually differentiating into cardiomyocyte-like cells. Conclusion: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.

Ankyrin-G heterozygous conditional knockout mice display increased sensitivity to social defeat stress

2021 ◽  
Author(s):  
Zachary A. Cordner ◽  
Seva G. Khambadkone ◽  
Shanshan Zhu ◽  
Justin Bai ◽  
Rasadokht Forati ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Social Defeat ◽  
Conditional Knockout ◽  
Social Defeat Stress ◽  
Conditional Knockout Mice ◽  
Ankyrin G ◽  
Increased Sensitivity
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