scholarly journals Zebrafish Paralogs brd2a and brd2b Are Needed for Proper Circulatory, Excretory and Central Nervous System Formation and Act as Genetic Antagonists during Development

2021 ◽  
Vol 9 (4) ◽  
pp. 46
Author(s):  
Gregory L. Branigan ◽  
Kelly S. Olsen ◽  
Isabella Burda ◽  
Matthew W. Haemmerle ◽  
Jason Ho ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Genetic Interaction ◽  
Homeobox Gene ◽  
Juvenile Myoclonic Epilepsy ◽  
Gene Promoters ◽  
Pronephric Duct ◽  
Spatiotemporal Expression ◽  
Morpholino Knockdown

Brd2 belongs to the BET family of epigenetic transcriptional co-regulators that act as adaptor-scaffolds for the assembly of chromatin-modifying complexes and other factors at target gene promoters. Brd2 is a protooncogene and candidate gene for juvenile myoclonic epilepsy in humans, a homeobox gene regulator in Drosophila, and a maternal-zygotic factor and cell death modulator that is necessary for normal development of the vertebrate central nervous system (CNS). As two copies of Brd2 exist in zebrafish, we use antisense morpholino knockdown to probe the role of paralog Brd2b, as a comparative study to Brd2a, the ortholog of human Brd2. A deficiency in either paralog results in excess cell death and dysmorphology of the CNS, whereas only Brd2b deficiency leads to loss of circulation and occlusion of the pronephric duct. Co-knockdown of both paralogs suppresses single morphant defects, while co-injection of morpholinos with paralogous RNA enhances them, suggesting novel genetic interaction with functional antagonism. Brd2 diversification includes paralog-specific RNA variants, a distinct localization of maternal factors, and shared and unique spatiotemporal expression, providing unique insight into the evolution and potential functions of this gene.

Hoxb1 controls effectors of sonic hedgehog and Mash1 signaling pathways

Development ◽  
2000 ◽  
Vol 127 (24) ◽  
pp. 5343-5354 ◽  
Author(s):  
G.O. Gaufo ◽  
P. Flodby ◽  
M.R. Capecchi
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Homeobox Gene ◽  
Targeted Disruption ◽  
Combined Actions

The diverse neuronal subtypes in the adult central nervous system arise from progenitor cells specified by the combined actions of anteroposterior (AP) and dorsoventral (DV) signaling molecules in the neural tube. Analyses of the expression and targeted disruption of the homeobox gene Hoxb1 demonstrate that it is essential for patterning progenitor cells along the entire DV axis of rhombomere 4 (r4). Hoxb1 accomplishes this function by acting very early during hindbrain neurogenesis to specify effectors of the sonic hedgehog and Mash1 signaling pathways. In the absence of Hoxb1 function, multiple neurons normally specified within r4 are instead programmed for early cell death. The findings reported here provide evidence for a genetic cascade in which an AP-specified transcription factor, Hoxb1, controls the commitment and specification of neurons derived from both alar and basal plates of r4.

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

2021 ◽  
Author(s):  
William E. Barclay ◽  
M. Elizabeth Deerhake ◽  
Makoto Inoue ◽  
Toshiaki Nonaka ◽  
Kengo Nozaki ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Animal Model ◽  
Cell Death ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

ABSTRACTInflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.

Metallothionein prevents neurodegeneration and central nervous system cell death after treatment with gliotoxin 6-aminonicotinamide

2004 ◽  
Vol 77 (1) ◽  
pp. 35-53 ◽  
Author(s):  
Milena Penkowa ◽  
Albert Quintana ◽  
Javier Carrasco ◽  
Mercedes Giralt ◽  
Amalia Molinero ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Central Nervous System Cell ◽  
System Cell

scholarly journals Anti-programmed cell death-1 (PD-1) monoclonal antibodies involve reversible cranial dura matter

2021 ◽  
Vol 2021 (9) ◽  
Author(s):  
Hiroshi Kataoka ◽  
Daisuke Shimada ◽  
Hitoki Nanaura ◽  
Kazuma Sugie
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Monoclonal Antibodies ◽  
Programmed Cell Death ◽  
Adverse Effects ◽  
Neuromuscular Disorders ◽  
Neurological Complications ◽  
Programmed Cell Death 1 ◽  
The Central Nervous System

ABSTRACT This case is the first document to describe a patient receiving anti-programmed cell death 1 (PD-1) antibodies which showed cranial dura matter involvement. According to the increasing use of anti-PD-1 monoclonal antibodies, adverse effects can occur in several organs since its ligand PD-L1 and PD-L2 are expressed in a wide variety of tissues. The estimated rate of neurological complications is 1–4.2% of patients, and neuromuscular disorders are the most common. Adverse effects on the central nervous system including encephalitis are less frequent. Here, a patient receiving anti-PD-1 antibodies showed cranial dura matter involvement, and the dura enhancement on MRI was resolved by withdrawal of the treatment with anti-PD-1 antibodies only.

The Drosophila SOX-domain protein Dichaete is required for the development of the central nervous system midline

Development ◽  
1998 ◽  
Vol 125 (20) ◽  
pp. 3989-3996 ◽  
Author(s):  
N.S. Soriano ◽  
S. Russell
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Genetic Interaction ◽  
Ventral Midline ◽  
Pou Domain ◽  
Dynamic Expression ◽  
The Central Nervous System ◽  
Sox Gene ◽  
Axonal Defects

SOX-domain proteins are a class of developmentally important transcriptional regulators related to the mammalian testis determining factor SRY. In common with other SOX-domain genes, the Drosophila Dichaete gene has a dynamic expression profile in the developing central nervous system, including cells of the ventral midline. We find defects in the differentiation of midline glia and concomitant axonal defects in Dichaete mutants that are rescued by driving Dichaete expression in the midline. Since Dichaete is required for the correct specification or differentiation of midline glia, we have used the ventral midline as a model system to study SOX gene function in vivo and demonstrate a genetic interaction between Dichaete and the POU domain gene ventral veinless. In mammals, a protein related to Dichaete, SOX2, also interacts with POU transcription factors. The midline phenotypes of Dichaete mutations are rescued by expression of mouse SOX2. Our data suggest that SOX gene structure, function and interactions have been conserved during evolution.

Efficacy of PD-1 or PD-L1 inhibitors and central nervous system metastases in advanced cancer: a meta-analysis

2021 ◽  
Vol 21 ◽  
Author(s):  
Minyong Peng ◽  
Shan Li ◽  
Hui Xiang ◽  
Wen Huang ◽  
Weiling Mao ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Overall Survival ◽  
Cell Death ◽  
Nervous System ◽  
Programmed Cell Death ◽  
Future Research ◽  
Significant Heterogeneity ◽  
Cns Metastases ◽  
Hazard Ratios ◽  
Significant Difference

<P>Background: Little is known about the efficacy of programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitors in patients with central nervous system (CNS) metastases. <P> Objective: Assess the difference in efficacy of PD-1 or PD-L1 inhibitors in patients with and without CNS metastases. <P> Methods: From inception to March 2020, PubMed and Embase were searched for randomized controlled trials (RCTs) about PD-1 or PD-L1 inhibitors. Only trails with available hazard ratios (HRs) for overall survival (OS) of patients with and without CNS metastases simultaneously would be included. Overall survival hazard ratios and their 95% confidence interval (CI) were calculated, and the efficacy difference between these two groups was assessed in the meantime. <P> Results: 4988 patients (559 patients with CNS metastases and 4429 patients without CNS metastases) from 8 RCTs were included. In patients with CNS metastases, the pooled HR was 0.76 (95%CI, 0.62 to 0.93), while in patients without CNS metastases, the pooled HR was 0.74 (95%CI, 0.68 to 0.79). There was no significant difference in efficacy between these two groups (Χ=0.06 P=0.80). <P> Conclusion: With no significant heterogeneity observed between patients with or without CNS metastases, patients with CNS metastases should not be excluded from PD-1 or PD-L1 blockade therapy. Future research should permit more patients with CNS metastases to engage in PD-1 or PD-L1 blockade therapy and explore the safety of PD-1 or PD-L1 inhibitors in patients with CNS metastases.</P>

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