Transcription factors Mash-1 and Prox-1 delineate early steps in differentiation of neural stem cells in the developing central nervous system

Development ◽  
1999 ◽  
Vol 126 (3) ◽  
pp. 443-456 ◽  
Author(s):  
M.a. Torii ◽  
F. Matsuzaki ◽  
N. Osumi ◽  
K. Kaibuchi ◽  
S. Nakamura ◽  
...  
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
Early Development ◽  
Molecular Mechanisms ◽  
Initial Step

Like other tissues and organs in vertebrates, multipotential stem cells serve as the origin of diverse cell types during genesis of the mammalian central nervous system (CNS). During early development, stem cells self-renew and increase their total cell numbers without overt differentiation. At later stages, the cells withdraw from this self-renewal mode, and are fated to differentiate into neurons and glia in a spatially and temporally regulated manner. However, the molecular mechanisms underlying this important step in cell differentiation remain poorly understood. In this study, we present evidence that the expression and function of the neural-specific transcription factors Mash-1 and Prox-1 are involved in this process. In vivo, Mash-1- and Prox-1-expressing cells were defined as a transient proliferating population that was molecularly distinct from self-renewing stem cells. By taking advantage of in vitro culture systems, we showed that induction of Mash-1 and Prox-1 coincided with an initial step of differentiation of stem cells. Furthermore, forced expression of Mash-1 led to the down-regulation of nestin, a marker for undifferentiated neuroepithelial cells, and up-regulation of Prox-1, suggesting that Mash-1 positively regulates cell differentiation. In support of these observations in vitro, we found specific defects in cellular differentiation and loss of expression of Prox-1 in the developing brain of Mash-1 mutant mice in vivo. Thus, we propose that induction of Mash-1 and Prox-1 is one of the critical molecular events that control early development of the CNS.

scholarly journals SUMO Represses Transcriptional Activity of the Drosophila SoxNeuro and Human Sox3 Central Nervous System–specific Transcription Factors

2005 ◽  
Vol 16 (6) ◽  
pp. 2660-2669 ◽  
Author(s):  
Jean Savare ◽  
Nathalie Bonneaud ◽  
Franck Girard
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Acceptor Site ◽  
Hmg Box ◽  
Sumo Modification

Sry high mobility group (HMG) box (Sox) transcription factors are involved in the development of central nervous system (CNS) in all metazoans. Little is known on the molecular mechanisms that regulate their transcriptional activity. Covalent posttranslational modification by small ubiquitin-like modifier (SUMO) regulates several nuclear events, including the transcriptional activity of transcription factors. Here, we demonstrate that SoxNeuro, an HMG box-containing transcription factor involved in neuroblast formation in Drosophila, is a substrate for SUMO modification. SUMOylation assays in HeLa cells and Drosophila S2 cells reveal that lysine 439 is the major SUMO acceptor site. The sequence in SoxNeuro targeted for SUMOylation, IKSE, is part of a small inhibitory domain, able to repress in cis the activity of two adjacent transcriptional activation domains. Our data show that SUMO modification represses SoxNeuro transcriptional activity in transfected cells. Overexpression in Drosophila embryos of a SoxN form that cannot be targeted for SUMOylation strongly impairs the development of the CNS, suggesting that SUMO modification of SoxN is crucial for regulating its activity in vivo. Finally, we present evidence that SUMO modification of group B1 Sox factors was conserved during evolution, because Sox3, the human counterpart of SoxN, is also negatively regulated through SUMO modification.

scholarly journals Adult mouse retina explants: an ex vivo window to explore central nervous system diseases

2020 ◽  
Author(s):  
Julia Schaeffer ◽  
Celine Tardy ◽  
Floriane Albert ◽  
Stephane Belin ◽  
Homaira Nawabi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Axon Regeneration ◽  
Ex Vivo ◽  
Adult Retina ◽  
Cellular Events ◽  
Embryonic Neurons

ABSTRACTWhen the developing central nervous system (CNS) becomes mature, it loses its ability to regenerate. Therefore, any insult to adult CNS leads to a permanent and irreversible loss of motor and cognitive functions. For a long time, much effort has been deployed to uncover mechanisms of axon regeneration in the CNS. It is now well understood that neurons themselves lose axon regeneration capabilities during development, and also after a lesion or in pathological conditions. Since then, many molecular pathways such as mTOR and JAK/STAT have been associated with axon regeneration. However, no functional recovery has been achieved yet. Today, there is a need not only to identify new molecules implicated in adult CNS axon regeneration, but also to decipher the fine molecular mechanisms associated with regeneration failure. This is critical to make progress in our understanding of neuroprotection and neuroregeneration and for the development of new therapeutic strategies. In this context, it remains particularly challenging to address molecular mechanisms in in vivo models of CNS regeneration. The extensive use of embryonic neurons as in vitro model is a source of bias, as they have the intrinsic competence to grow their axon upon injury, unlike mature neurons. In addition, this type of dissociated neuronal cultures lack a tissue environment to recapitulate properly molecular and cellular events in vitro. Here, we propose to use cultures of adult retina explants to fill this gap. The visual system - which includes the retina and optic nerve - is a gold-standard model to study axon regeneration and degeneration in the mature CNS. Cultures of adult retina explants combine two advantages: they have the simplicity of embryonic neurons cultures and they recapitulate all the aspects of in vivo features in the tissue. Importantly, it is the most appropriate tool to date to isolate molecular and cellular events of axon regeneration and degeneration of the adult CNS in a dish. This ex vivo system allows to set up a large range of experiments to decipher the fine molecular and cellular regulations underlying mature CNS axon growth.

New Design Of Human T-ALL Transplantation In NSG Mice Uncovers The Major Role Of CD31/PECAM1 In The Central Nervous System Infiltration

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1436-1436
Author(s):  
Sandrine Poglio ◽  
Anne-Laure Bauchet ◽  
José Ramon Pineda ◽  
Caroline Deswarte ◽  
Thierry Leblanc ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Receptor Expression ◽  
Leukemic Cells ◽  
Nsg Mice ◽  
Increased Risk ◽  
Major Player

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is mainly a child and adolescent blood malignancy. T-ALL patients present an increased risk of Central Nervous System (CNS) relapse defined by leukemic cell infiltration in cerebrospinal fluid and brain. Using transgenic mice and T-ALL cell lines previous works have shown that T-ALL migration in CNS depends on CCR7 chemokine receptor expression (S. Buonamici et al., Nature, 2009). VE-cadherin and CD31/PECAM1 also seem implicated, as it has been shown in vitro (S. M. Akers et al., Exp Hematol, 2010). In patients, high level of IL-15 at diagnosis predicts current CNS invasion and sometimes at relapse (G. Cario et al., J Clin Oncol, 2007). So far no study has investigated mechanisms involved in CNS infiltration using T-ALL patient samples in vivo. In the present study we developed a mouse model of CNS infiltration using leukemic cells isolated from patients and transplanted into NOD/SCID IL2Rуc-/- (NSG) mice. Proper conditioning of NSG mice and different routes of injection were tested to define a protocol avoiding non-specific CNS infiltration of leukemic cells. Also bone marrow (BM) engraftment levels of leukemia between 60 to 100% were used to set up the excision time of hematopoietic tissues and brain. Leukemic blasts from 8 patients with or 9 patients without CNS invasion were grafted and brain infiltration was followed up using standard histology and immunohistochemistry techniques. Our data indicate that (1) under specific experimental procedures, leukemic cells from patients with CNS invasion did infiltrate mouse CNS (8/8 samples) whereas the majority of cells from “non-infiltrated” patients did not (7/9 samples), (2) leukemic cells recovered from NSG brain and BM were similar in terms of brain and/or BM infiltration in secondary transplant experiments. Moreover, T-Leukemia Initiating Cell frequency was the same whatever the BM or CNS origin of blasts in the primary recipient. Interestingly, analysis of blasts at diagnosis showed that surface expression of adhesion molecules can not discriminate CNS+ or CNS- leukemic cells. However, blocking of CD31 decreased in vitro migration of blasts from CNS+ compared to CNS- patients through endothelial layer derived from blood brain barrier cells. Pioneered in vivo experiments show that CNS+ blasts pre-treated with CD31 antibody and injected in NSG are less prone to colonize mouse brain. Moreover, knocking down CD31 in CNS+ T-ALL by lentiviral shRNA strategy impairs leukemia development in mice, further decreasing CNS infiltration, whatever injection routes is used including intrafemoral injection. In conclusion, T-ALL xenografts in NSG mice mimic CNS invasion in patients. CD31 is a major player in blast cells migration in vitro and brain infiltration in vivo. This new model opens a new area of investigation to improve our knowledge of the molecular mechanisms of CNS infiltration in T-ALL. Disclosures: No relevant conflicts of interest to declare.

Neural Stem Cells to Glial Cells an Important Factor for Brain Injury

2020 ◽  
Author(s):  
Prithiv K R Kumar
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Neural Stem Cells ◽  
Glial Cells ◽  
Brain Injuries ◽  
The Body ◽  
The Central Nervous System ◽  
Near Future

Stem cells have the capacity to differentiate into any type of cell or organ. Stems cell originate from any part of the body, including the brain. Brain cells or rather neural stem cells have the capacitive advantage of differentiating into the central nervous system leading to the formation of neurons and glial cells. Neural stem cells should have a source by editing DNA, or by mixings chemical enzymes of iPSCs. By this method, a limitless number of neuron stem cells can be obtained. Increase in supply of NSCs help in repairing glial cells which in-turn heal the central nervous system. Generally, brain injuries cause motor and sensory deficits leading to stroke. With all trials from novel therapeutic methods to enhanced rehabilitation time, the economy and quality of life is suppressed. Only PSCs have proven effective for grafting cells into NSCs. Neurons derived from stem cells is the only challenge that limits in-vitro usage in the near future.

scholarly journals Regulation of sarcomagenesis by the empty spiracles homeobox genes EMX1 and EMX2

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Manuel Pedro Jimenez-García ◽  
Antonio Lucena-Cacace ◽  
Daniel Otero-Albiol ◽  
Amancio Carnero
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Neural Crest ◽  
Tumor Suppressors ◽  
Homeobox Genes ◽  
Neuronal Cell ◽  
Cell Gene Expression

AbstractThe EMX (Empty Spiracles Homeobox) genes EMX1 and EMX2 are two homeodomain gene members of the EMX family of transcription factors involved in the regulation of various biological processes, such as cell proliferation, migration, and differentiation, during brain development and neural crest migration. They play a role in the specification of positional identity, the proliferation of neural stem cells, and the differentiation of certain neuronal cell phenotypes. In general, they act as transcription factors in early embryogenesis and neuroembryogenesis from metazoans to higher vertebrates. The EMX1 and EMX2’s potential as tumor suppressor genes has been suggested in some cancers. Our work showed that EMX1/EMX2 act as tumor suppressors in sarcomas by repressing the activity of stem cell regulatory genes (OCT4, SOX2, KLF4, MYC, NANOG, NES, and PROM1). EMX protein downregulation, therefore, induced the malignance and stemness of cells both in vitro and in vivo. In murine knockout (KO) models lacking Emx genes, 3MC-induced sarcomas were more aggressive and infiltrative, had a greater capacity for tumor self-renewal, and had higher stem cell gene expression and nestin expression than those in wild-type models. These results showing that EMX genes acted as stemness regulators were reproduced in different subtypes of sarcoma. Therefore, it is possible that the EMX genes could have a generalized behavior regulating proliferation of neural crest-derived progenitors. Together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-altering populations or cancer stem cells, acting as tumor suppressors in sarcoma.

scholarly journals Expression Profile of New Marker Genes Involved in Differentiation of Canine Adipose-Derived Stem Cells into Osteoblasts

2021 ◽  
Vol 22 (13) ◽  
pp. 6663
Author(s):  
Maurycy Jankowski ◽  
Mariusz Kaczmarek ◽  
Grzegorz Wąsiatycz ◽  
Claudia Dompe ◽  
Paul Mozdziak ◽  
...  
Keyword(s):  
Stem Cells ◽  
In Vitro Culture ◽  
Osteogenic Differentiation ◽  
Molecular Mechanisms ◽  
Marker Genes ◽  
P Value ◽  
Illumina Platform

Next-generation sequencing (RNAseq) analysis of gene expression changes during the long-term in vitro culture and osteogenic differentiation of ASCs remains to be important, as the analysis provides important clues toward employing stem cells as a therapeutic intervention. In this study, the cells were isolated from adipose tissue obtained during routine surgical procedures and subjected to 14-day in vitro culture and differentiation. The mRNA transcript levels were evaluated using the Illumina platform, resulting in the detection of 19,856 gene transcripts. The most differentially expressed genes (fold change >|2|, adjusted p value < 0.05), between day 1, day 14 and differentiated cell cultures were extracted and subjected to bioinformatical analysis based on the R programming language. The results of this study provide molecular insight into the processes that occur during long-term in vitro culture and osteogenic differentiation of ASCs, allowing the re-evaluation of the roles of some genes in MSC progression towards a range of lineages. The results improve the knowledge of the molecular mechanisms associated with long-term in vitro culture and differentiation of ASCs, as well as providing a point of reference for potential in vivo and clinical studies regarding these cells’ application in regenerative medicine.

scholarly journals INFLUENCE OF ANESTHESIA ON EXPERIMENTAL NEUROTROPIC VIRUS INFECTIONS

1946 ◽  
Vol 84 (4) ◽  
pp. 277-292 ◽  
Author(s):  
S. Edward Sulkin ◽  
Christine Zarafonetis ◽  
Andres Goth
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Diethyl Ether ◽  
Cervical Region ◽  
Virus Infections ◽  
Ether Anesthesia ◽  
Neurotropic Virus ◽  
Experimental Infections

Anesthesia with diethyl ether significantly alters the course and outcome of experimental infections with the equine encephalomyelitis virus (Eastern or Western type) or with the St. Louis encephalitis virus. No comparable effect is observed in experimental infections produced with rabies or poliomyelitis (Lansing) viruses. The neurotropic virus infections altered by ether anesthesia are those caused by viruses which are destroyed in vitro by this anesthetic, and those infections not affected by ether anesthesia are caused by viruses which apparently are not destroyed by ether in vitro. Another striking difference between these two groups of viruses is their pathogenesis in the animal host; those which are inhibited in vivo by ether anesthesia tend to infect cells of the cortex, basal ganglia, and only occasionally the cervical region of the cord. On the other hand, those which are not inhibited in vivo by ether anesthesia tend to involve cells of the lower central nervous system and in the case of rabies, peripheral nerves. This difference is of considerable importance in view of the fact that anesthetics affect cells of the lower central nervous system only in very high concentrations. It is obvious from the complexity of the problem that no clear-cut statement can be made at this point as to the mechanism of the observed effect of ether anesthesia in reducing the mortality rate in certain of the experimental neurotropic virus infections. Important possibilities include a direct specific effect of diethyl ether upon the virus and a less direct effect of the anesthetic upon the virus through its alteration of the metabolism of the host cell.

scholarly journals Astrocyte-Derived CCL2 is Associated with M1 Activation and Recruitment of Cultured Microglial Cells

2016 ◽  
Vol 38 (3) ◽  
pp. 859-870 ◽  
Author(s):  
Mingfeng He ◽  
Hongquan Dong ◽  
Yahui Huang ◽  
Shunmei Lu ◽  
Shu Zhang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Microglial Activation ◽  
Culture Media ◽  
Microglial Cells ◽  
Migration Ability ◽  
Migration Assay ◽  
Tnf Α

Background/Aims: Microglia are an essential player in central nervous system inflammation. Recent studies have demonstrated that the astrocytic chemokine, CCL2, is associated with microglial activation in vivo. However, CCL2-induced microglial activation has not yet been studied in vitro. The purpose of the current study was to understand the role of astrocyte-derived CCL2 in microglial activation and to elucidate the underlying mechanism(s). Methods: Primary astrocytes were pre-treated with CCL2 siRNA and stimulated with TNF-α. The culture medium (CM) was collected and added to cultures of microglia, which were incubated with and without CCR2 inhibitor. Microglial cells were analyzed by quantitative RT-PCR to determine whether they polarized to the M1 or M2 state. Microglial migratory ability was assessed by transwell migration assay. Results: TNF-α stimulated the release of CCL2 from astrocytes, even if the culture media containing TNF-α was replaced with fresh media after 3 h. CM from TNF-α-stimulated astrocytes successfully induced microglial activation, which was ascertained by increased activation of M1 and enhanced migration ability. In contrast, CM from astrocytes pretreated with CCL2 siRNA showed no effect on microglial activation, compared to controls. Additionally, microglia pre-treated with RS102895, a CCR2 inhibitor, were resistant to activation by CM from TNF-α-stimulated astrocytes. Conclusion: This study demonstrates that the CCL2/CCR2 pathway of astrocyte-induced microglial activation is associated with M1 polarization and enhanced migration ability, indicating that this pathway could be a useful target to ameliorate inflammation in the central nervous system.

scholarly journals Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)

2018 ◽  
Vol 5 (4) ◽  
pp. 96 ◽  
Author(s):  
Anders Bailey ◽  
Amreena Suri ◽  
Pauline Chou ◽  
Tatiana Pundy ◽  
Samantha Gadd ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Tumors ◽  
Meta Analysis ◽  
P Value ◽  
Embryonal Tumors ◽  
Expression Levels ◽  
Embryonal Brain

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB.

scholarly journals PTMAc-PEG-PTMAc hydrogel modified by RGDC and hyaluronic acid promotes neural stem cells' survival and differentiation in vitro

RSC Advances ◽  
2017 ◽  
Vol 7 (65) ◽  
pp. 41098-41104 ◽  
Author(s):  
Ruirui Yang ◽  
Caixia Xu ◽  
Tao Wang ◽  
Yuanqi Wang ◽  
Jingnan Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Hyaluronic Acid ◽  
Neural Stem Cells ◽  
Biological Properties ◽  
Central Nervous System Injury ◽  
Bioactive Molecules

The enhancement of the biological properties of hydrogels by surface modifying with bioactive molecules is of great significance, especially for the treatment of central nervous system injury by combining engrafted cells.

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