Loss of PP2A Disrupts the Retention of Radial Glial Progenitors in the Telencephalic Niche to Impair the Generation for Late-Born Neurons During Cortical Development†

2020 ◽  
Vol 30 (7) ◽  
pp. 4183-4196
Author(s):  
Chaoli Huang ◽  
Tingting Liu ◽  
Qihui Wang ◽  
Weikang Hou ◽  
Cuihua Zhou ◽  
...  
Keyword(s):  
Neural Progenitor Cells ◽  
Ventricular Zone ◽  
Cortical Development ◽  
Underlying Mechanism ◽  
Conditional Knockout ◽  
Glial Progenitors ◽  
Radial Glial ◽  
Vitro Analysis ◽  
The Impact

Abstract Telencephalic radial glial progenitors (RGPs) are retained in the ventricular zone (VZ), the niche for neural stem cells during cortical development. However, the underlying mechanism is not well understood. To study whether protein phosphatase 2A (PP2A) may regulate the above process, we generate Ppp2cα conditional knockout (cKO) mice, in which PP2A catalytic subunit α (PP2Acα) is inactivated in neural progenitor cells in the dorsal telencephalon. We show that RGPs are ectopically distributed in cortical areas outside of the VZ in Ppp2cα cKO embryos. Whereas deletion of PP2Acα does not affect the proliferation of RGPs, it significantly impairs the generation of late-born neurons. We find complete loss of apical adherens junctions (AJs) in the ventricular membrane in Ppp2cα cKO cortices. We observe abundant colocalization for N-cadherin and PP2Acα in control AJs. Moreover, in vitro analysis reveals direct interactions of N-cadherin to PP2Acα and to β-catenin. Overall, this study not only uncovers a novel function of PP2Acα in retaining RGPs into the VZ but also demonstrates the impact of PP2A-dependent retention of RGPs on the generation for late-born neurons.

scholarly journals RhoG Promotes Neural Progenitor Cell Proliferation in Mouse Cerebral Cortex

2009 ◽  
Vol 20 (23) ◽  
pp. 4941-4950 ◽  
Author(s):  
Satoshi Fujimoto ◽  
Manabu Negishi ◽  
Hironori Katoh
Keyword(s):  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Ventricular Zone ◽  
Cortical Development ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Brdu Incorporation ◽  
Progenitor Cell Proliferation

In early cortical development, neural progenitor cells (NPCs) expand their population in the ventricular zone (VZ), and produce neurons. Although a series of studies have revealed the process of neurogenesis, the molecular mechanisms regulating NPC proliferation are still largely unknown. Here we found that RhoG, a member of Rho family GTPases, was expressed in the VZ at early stages of cortical development. Expression of constitutively active RhoG promoted NPC proliferation and incorporation of bromodeoxyuridine (BrdU) in vitro, and the proportion of Ki67-positive cells in vivo. In contrast, knockdown of RhoG by RNA interference suppressed the proliferation, BrdU incorporation, and the proportion of Ki67-positive cells in NPCs. However, knockdown of RhoG did not affect differentiation and survival of NPC. The RhoG-induced promotion of BrdU incorporation required phosphatidylinositol 3-kinase (PI3K) activity but not the interaction with ELMO. Taken together, these results indicate that RhoG promotes NPC proliferation through PI3K in cortical development.

scholarly journals Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 210-223 ◽  
Author(s):  
Eun Ji Gang ◽  
Hye Na Kim ◽  
Yao-Te Hsieh ◽  
Yongsheng Ruan ◽  
Heather A. Ogana ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Underlying Mechanism ◽  
Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

scholarly journals Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Lifeng Feng ◽  
Miaoqin Chen ◽  
Yiling Li ◽  
Muchun Li ◽  
Shiman Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Cell Growth ◽  
Knockout Mice ◽  
Liver Tumors ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Conditional Knockout

Abstractp62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

The Impact of Scaphoid Malunion on Carpal Motion: An In-Vitro Analysis

2021 ◽  
Author(s):  
Spencer B. Chambers ◽  
Clare E. Padmore ◽  
Stacy Fan ◽  
Ruby Grewal ◽  
James Johnson ◽  
...  
Keyword(s):  
Vitro Analysis ◽  
The Impact ◽  
In Vitro Analysis

Stromal derived factor-1α in hippocampus radial glial cells in vitro regulates the migration of neural progenitor cells

2015 ◽  
Vol 39 (6) ◽  
pp. 750-758 ◽  
Author(s):  
Hui Ding ◽  
Guo-Hua Jin ◽  
Lin-Qing Zou ◽  
Xiao-Qing Zhang ◽  
Hao-Ming Li ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Glial Cells ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Radial Glial Cells ◽  
Radial Glial

Grb10 Mediated Akt Activation Is Required for Induction of CML Like Myeloproliferative Disease in Mice by BCR-ABL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1012-1012
Author(s):  
Corinna Albers ◽  
Anna L. Illert ◽  
Cornelius Miething ◽  
Christian Peschel ◽  
Justus Duyster
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinases ◽  
Chromosomal Translocation ◽  
Control Group ◽  
Myeloproliferative Disease ◽  
Hematopoietic Stem ◽  
Murine Bone Marrow ◽  
Vitro Analysis ◽  
The Impact

Abstract Chronic myelogenous leukaemia (CML) results from the neoplastic transformation of hematopoietic stem cells (HSC) and is characterized by a chromosomal translocation t(9;22)(q34;q11). This aberration leads to the expression of the oncogenic tyrosine kinase BCR-ABL, which mediates signals for proliferation, transformation and anti-apoptosis via various signalling pathways. Grb10, a member of the growth factor bound proteins, is known to bind activated tyrosine kinases like BCR-ABL and might be involved in the activation of the Akt signalling pathway. Here we report the impact of Grb10 for BCR-ABL mediated transformation. We exerted a siRNA based approach in combination with a murine bone marrow transplantation model. To this end we designed a MSCV based retrovirus encoding both a Grb10 microRNA and the BCR-ABL oncogene on a single construct. This approach ensured knockdowns of more than 90% in every BCR-ABL transformed cell. Methylcellulose assays demonstrated that bone marrow coexpressing Grb10 microRNA and BCR-ABL had a 4-fold decreased colony forming ability compared to control cells. We then transduced bone marrow (BM) with retrovirus coexpressing Grb10 microRNA and p185 BCR-ABL and transplanted lethally irradiated recipient Balb/C mice. The onset and progression of leukaemia was significantly delayed in mice transplanted with Grb10 microRNA and BCR-ABL compared with the BCR-ABL transduced control microRNA group. However, we were not able to completely avoid the development of leukaemia by Grb10 knockdown. Mice transplanted with the Grb10 knockdown construct showed a delayed lymphoblastic disease, positive for B220, whereas the control group developed a rapid myeloproliferative disease, characterized by CD11b and Gr-1. In vitro analysis of BaF/3 and 32D cells showed that Grb10 knockdown in combination with BCR-ABL expression leads to a reduced phosphorylation of Akt. Taken together our data demonstrate that Grb10 is required for the development of a myeloproliferative disease by BCR-ABL in mice. Hereby, Grb10 seems to be critical for the BCR-ABL induced activation of the Akt pathway. In addition, this study describes a novel approach to express an oncogene and a microRNA using a single retroviral construct. This tool can be used to systematically screen for drugable signalling targets involved in oncogenesis.

scholarly journals miR-96 Regulates Liver Tumor-Initiating Cells Expansion and Sorafenib Resistance

2020 ◽  
Author(s):  
Yonggang Huang ◽  
Jin Zhang ◽  
Wei Dong ◽  
Huiping Peng ◽  
Maolin Gu ◽  
...  
Keyword(s):  
Liver Tumor ◽  
Underlying Mechanism ◽  
Tumor Initiating Cells ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
Functional Studies ◽  
Optimal Target ◽  
The Impact

Abstract Background Liver tumor-initiating cells (T-ICs) contribute to tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Methods Real-time PCR was used to detect the expression of miR-96 in liver tumor-initiating cells (T-ICs). The impact of miR-96 on liver T-ICs expansion was investigated both in vivo and in vitro . The correlation between miR-96 expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results Our finding shows that miR-96 is upregulated in liver T-ICs. Functional studies revealed that forced miR-96 promotes liver T-ICs self-renewal and tumorigenesis. Conversely, knockdown miR-96 inhibits liver T-ICs self-renewal and tumorigenesis. Mechanistically, miR-96 downregulates SOX6 via its mRNA 3’UTR in liver T-ICs. Furthermore, the miR-96 expression determines the responses of hepatoma cells to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-96 may predict sorafenib benefits in HCC patients. Conclusion Our findings revealed the crucial role of the miR-96 in liver T-ICs expansion and sorafenib response, rendering miR-96 as an optimal target for the prevention and intervention of HCC.

Inhibitory effects of Atlantic cod (Gadus morhua) peptides on RANKL-induced osteoclastogenesis in vitro and osteoporosis in ovariectomized mice

2022 ◽  
Author(s):  
Meilian Yang ◽  
Di Wu ◽  
Shuzhen Cheng ◽  
Yu Dong ◽  
Chao Wu ◽  
...  
Keyword(s):  
Nutritional Value ◽  
Gadus Morhua ◽  
Atlantic Cod ◽  
Economic Value ◽  
Underlying Mechanism ◽  
Inhibitory Effects ◽  
Ovariectomized Mice ◽  
The World ◽  
The Impact

Atlantic cod (Gadus morhua) is one of the most important fishes in the world with high nutritional value and economic value. However, the impact and underlying mechanism of the G....

scholarly journals Periventricular Heterotopia: Shuttling of Proteins through Vesicles and Actin in Cortical Development and Disease

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Volney L. Sheen
Keyword(s):  
Cell Fate ◽  
Brain Size ◽  
Ventricular Zone ◽  
Cortical Development ◽  
Cell Fate Decisions ◽  
Cytoskeletal Network ◽  
Malformation Of Cortical Development ◽  
Periventricular Heterotopia ◽  
Mature Neurons ◽  
Radial Glial

During cortical development, proliferating neural progenitors exhibit polarized apical and basolateral membranes that are maintained by tightly controlled and membrane-specific vesicular trafficking pathways. Disruption of polarity through impaired delivery of proteins can alter cell fate decisions and consequent expansion of the progenitor pool, as well as impact the integrity of the neuroependymal lining. Loss of neuroependymal integrity disrupts radial glial scaffolding and alters initial neuronal migration from the ventricular zone. Vesicle trafficking is also required for maintenance of lipid and protein cycling within the leading and trailing edge of migratory neurons, as well as dendrites and synapses of mature neurons. Defects in this transport machinery disrupt neuronal identity, migration, and connectivity and give rise to a malformation of cortical development termed as periventricular heterotopia (PH). PH is characterized by a reduction in brain size, ectopic clusters of neurons localized along the lateral ventricle, and epilepsy and dyslexia. These anatomical anomalies correlate with developmental impairments in neural progenitor proliferation and specification, migration from loss of neuroependymal integrity and neuronal motility, and aberrant neuronal process extension. Genes causal for PH regulate vesicle-mediated endocytosis along an actin cytoskeletal network. This paper explores the role of these dynamic processes in cortical development and disease.

scholarly journals Natural variation in gene expression and Zika virus susceptibility revealed by villages of neural progenitor cells

2021 ◽  
Author(s):  
Michael F Wells ◽  
James Nemesh ◽  
Sulagna Ghosh ◽  
Jana M Mitchell ◽  
Curtis J Mello ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Progenitor Cells ◽  
Zika Virus ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Virus Infectivity ◽  
Cellular Mechanisms ◽  
Natural Genetic Variation ◽  
The Impact

Variation in the human genome contributes to abundant diversity in human traits and vulnerabilities, but the underlying molecular and cellular mechanisms are not yet known, and will need scalable approaches to accelerate their recognition. Here, we advanced and applied an experimental platform that analyzes genetic, molecular, and phenotypic heterogeneity across cells from very many human donors cultured in a single, shared in vitro environment, with algorithms (Dropulation and Census-seq) for assigning phenotypes to individual donors. We used natural genetic variation and synthetic (CRISPR-Cas9) genetic perturbations to analyze the vulnerability of neural progenitor cells to infection with Zika virus. These analyses identified a common variant in the antiviral IFITM3 gene that regulated IFITM3 expression and explained most inter-individual variation in NPCs' susceptibility to Zika virus infectivity. These and other approaches could provide scalable ways to recognize the impact of genes and genetic variation on cellular phenotypes.

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