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.

scholarly journals mTORC2 loss in oligodendrocyte progenitor cells results in regional hypomyelination in the central nervous system

2022 ◽  
Author(s):  
Kristin D Dahl ◽  
Hannah A Hathaway ◽  
Adam R Almeida ◽  
Jennifer Bourne ◽  
Tanya L Brown ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Corpus Callosum ◽  
Signaling Pathways ◽  
Progenitor Cells ◽  
Myelin Proteins ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
The Central Nervous System

In the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) differentiate into mature oligodendrocytes to generate myelin, which is essential for normal nervous system function. OPC differentiation is driven by signaling pathways such as mTOR (Mechanistic Target of Rapamycin), which functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), containing Raptor or Rictor respectively. In the current studies, mTORC2 signaling was selectively deleted from OPCs in PDGFRα-Cre X Rictorfl/fl mice. This study examined developmental myelination in male and female mice, comparing the impact of mTORC2 deletion in the corpus callosum and spinal cord. In both corpus callosum and spinal cord, Rictor loss in OPCs resulted in early reduction in myelin RNAs and some myelin proteins. However, these deficits rapidly recovered in spinal cord, where normal myelin abundance and thickness was noted at post-natal day 21 and 1.5 months. By contrast, the losses in corpus callosum resulted in severe hypomyelination, and increased unmyelinated axons. The current studies focus on uniquely altered signaling pathways following mTORC2 loss in developing oligodendrocytes. A major mTORC2 substrate is phospho-Akt-S473, which was significantly reduced throughout development in both corpus callosum and spinal cord at all ages measured, yet this had little impact in spinal cord. Loss of mTORC2 signaling resulted in decreased expression of actin regulators such as gelsolin in corpus callosum, but only minimal loss in spinal cord. The current study establishes a regionally-specific role for mTORC2 signaling in OPCs, particularly in the corpus callosum.

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.

Crosstalk Between Insulin and Toll-like Receptor Signaling Pathways in the Central Nervous system

2014 ◽  
Vol 50 (3) ◽  
pp. 797-810 ◽  
Author(s):  
Fatemeh Hemmati ◽  
Rasoul Ghasemi ◽  
Norlinah Mohamed Ibrahim ◽  
Leila Dargahi ◽  
Zahurin Mohamed ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Signaling Pathways ◽  
Receptor Signaling ◽  
Toll Like Receptor ◽  
The Central Nervous System

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
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