scholarly journals A role for the orphan nuclear receptor TLX in the interaction between neural precursor cells and microglia

2019 ◽  
Vol 3 (1) ◽  
Author(s):  
Danka A. Kozareva ◽  
Gerard M. Moloney ◽  
Alan E. Hoban ◽  
Valerio Rossini ◽  
Ken Nally ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Cross Talk ◽  
Molecular Mechanisms ◽  
Hippocampal Neurogenesis ◽  
Neural Precursor ◽  
Orphan Nuclear Receptor ◽  
Altered Expression ◽  
Neurogenic Niche ◽  
Signalling Molecules ◽  
Newborn Neurons

Abstract Microglia are an essential component of the neurogenic niche in the adult hippocampus and are involved in the control of neural precursor cell (NPC) proliferation, differentiation and the survival and integration of newborn neurons in hippocampal circuitry. Microglial and neuronal cross-talk is mediated in part by the chemokine fractalkine/chemokine (C-X3-C motif) ligand 1 (CX3CL1) released from neurons, and its receptor CX3C chemokine receptor 1 (CX3CR1) which is expressed on microglia. A disruption in this pathway has been associated with impaired neurogenesis yet the specific molecular mechanisms by which this interaction occurs remain unclear. The orphan nuclear receptor TLX (Nr2e1; homologue of the Drosophila tailless gene) is a key regulator of hippocampal neurogenesis, and we have shown that in its absence microglia exhibit a pro-inflammatory activation phenotype. However, it is unclear whether a disturbance in CX3CL1/CX3CR1 communication mediates an impairment in TLX-related pathways which may have subsequent effects on neurogenesis. To this end, we assessed miRNA expression of up- and down-stream signalling molecules of TLX in the hippocampus of mice lacking CX3CR1. Our results demonstrate that a lack of CX3CR1 is associated with altered expression of TLX and its downstream targets in the hippocampus without significantly affecting upstream regulators of TLX. Thus, TLX may be a potential participant in neural stem cell (NSC)–microglial cross-talk and may be an important target in understanding inflammatory-associated impairments in neurogenesis.

scholarly journals The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

2014 ◽  
Vol 53 (1) ◽  
pp. 43-55 ◽  
Author(s):  
Raifish E Mendoza-Villarroel ◽  
Mickaël Di-Luoffo ◽  
Etienne Camiré ◽  
Xavier C Giner ◽  
Catherine Brousseau ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Protein Interactions ◽  
Leydig Cells ◽  
Molecular Mechanisms ◽  
Direct Repeat ◽  
Testicular Descent ◽  
Mrna Levels ◽  
Orphan Nuclear Receptor ◽  
Protein Protein Interactions ◽  
Dna Precipitation

Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance, little is known about the molecular mechanisms controlling INSL3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), an orphan nuclear receptor known to play critical roles in cell differentiation and lineage determination in several tissues. Although COUP-TFII-deficient mice had Leydig cell dysfunction and impaired fertility, it remained unknown whether Insl3 expression was directly regulated by COUP-TFII. In this study, we observed a significant decrease in Insl3 mRNA levels in MA-10 Leydig cells depleted of COUP-TFII. Furthermore, a −1087 bp mouse Insl3 promoter was activated fourfold by COUP-TFII in MA-10 Leydig cells. Using 5′ progressive deletions, the COUP-TFII-responsive element was located between −186 and −79 bp, a region containing previously uncharacterised direct repeat 0-like (DR0-like) and DR3 elements. The recruitment and direct binding of COUP-TFII to the DR0-like element were confirmed by chromatin immunoprecipitation and DNA precipitation assay respectively. Mutation of the DR0-like element, which prevented COUP-TFII binding, significantly decreased COUP-TFII-mediated activation of the −1087 bp Insl3 reporter in CV-1 fibroblast cells but not in MA-10 Leydig cells. Finally, we found that COUP-TFII cooperates with the nuclear receptor steroidogenic factor 1 (SF1) to further enhance Insl3 promoter activity. Our results identify Insl3 as a target for COUP-TFII in Leydig cells and revealed that COUP-TFII acts through protein–protein interactions with other DNA-bound transcription factors, including SF1, to activate Insl3 transcription in these cells.

ERα/E2 signaling suppresses the expression of steroidogenic enzyme genes via cross-talk with orphan nuclear receptor Nur77 in the testes

2012 ◽  
Vol 362 (1-2) ◽  
pp. 91-103 ◽  
Author(s):  
Seung-Yon Lee ◽  
Eunsook Park ◽  
Seung-Chang Kim ◽  
Ryun-Sup Ahn ◽  
CheMyong Ko ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Cross Talk ◽  
Orphan Nuclear Receptor ◽  
Steroidogenic Enzyme

scholarly journals TRAP/SMCC/Mediator-Dependent Transcriptional Activation from DNA and Chromatin Templates by Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4

2002 ◽  
Vol 22 (15) ◽  
pp. 5626-5637 ◽  
Author(s):  
Sohail Malik ◽  
Annika E. Wallberg ◽  
Yun Kyoung Kang ◽  
Robert G. Roeder
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Strong Dependence ◽  
Physical Interaction ◽  
Nuclear Factor ◽  
Orphan Nuclear Receptor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4

ABSTRACT The orphan nuclear receptor hepatocyte nuclear factor 4 (HNF-4) regulates the expression of many liver-specific genes both during development and in the adult animal. Towards understanding the molecular mechanisms by which HNF-4 functions, we have established in vitro transcription systems that faithfully recapitulate HNF-4 activity. Here we have focused on the coactivator requirements for HNF-4, especially for the multicomponent TRAP/SMCC/Mediator complex that has emerged as the central regulatory module of the transcription apparatus. Using a system that has been reconstituted from purified transcription factors, as well as one consisting of unfractionated nuclear extract from which TRAP/SMCC/Mediator has been depleted by specific antibodies, we demonstrate a strong dependence of HNF-4 function on this coactivator. Importantly, we further show a TRAP/SMCC/Mediator-dependence for HNF-4 transcriptional activation from chromatin templates. The latter involves cooperation with the histone acetyltransferase-containing coactivator p300, in accord with a synergistic mode of action of the two divergent coactivators. We also show that HNF-4 and TRAP/SMCC/Mediator can interact physically. This interaction likely involves primary HNF-4 activation function 2 (AF-2)-dependent interactions with the TRAP220 subunit of TRAP/SMCC/Mediator and secondary (AF-2-independent) interactions with TRAP170/RGR1. Finally, recruitment experiments using immobilized templates strongly suggest that the functional consequences of the physical interaction probably are manifested at a postrecruitment step in the activation pathway.

scholarly journals Chronic stress induces significant gene expression changes in the prefrontal cortex alongside alterations in adult hippocampal neurogenesis

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Ksenia Musaelyan ◽  
Selin Yildizoglu ◽  
James Bozeman ◽  
Andrea Du Preez ◽  
Martin Egeland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Chronic Stress ◽  
Molecular Mechanisms ◽  
Dendritic Tree ◽  
Hippocampal Neurogenesis ◽  
Stress Disorders ◽  
Adult Hippocampal Neurogenesis ◽  
Mild Stress ◽  
Neurogenic Niche

Abstract Adult hippocampal neurogenesis is involved in stress-related disorders such as depression, posttraumatic stress disorders, as well as in the mechanism of antidepressant effects. However, the molecular mechanisms involved in these associations remain to be fully explored. In this study, unpredictable chronic mild stress in mice resulted in a deficit in neuronal dendritic tree development and neuroblast migration in the hippocampal neurogenic niche. To investigate molecular pathways underlying neurogenesis alteration, genome-wide gene expression changes were assessed in the prefrontal cortex, hippocampus and the hypothalamus alongside neurogenesis changes. Cluster analysis showed that the transcriptomic signature of chronic stress is much more prominent in the prefrontal cortex compared to the hippocampus and the hypothalamus. Pathway analyses suggested huntingtin, leptin, myelin regulatory factor, methyl-CpG binding protein and brain-derived neurotrophic factor as the top predicted upstream regulators of transcriptomic changes in the prefrontal cortex. Involvement of the satiety regulating pathways (leptin) was corroborated by behavioural data showing increased food reward motivation in stressed mice. Behavioural and gene expression data also suggested circadian rhythm disruption and activation of circadian clock genes such as Period 2. Interestingly, most of these pathways have been previously shown to be involved in the regulation of adult hippocampal neurogenesis. It is possible that activation of these pathways in the prefrontal cortex by chronic stress indirectly affects neuronal differentiation and migration in the hippocampal neurogenic niche via reciprocal connections between the two brain areas.

scholarly journals Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

2020 ◽  
Author(s):  
Evgenia Salta ◽  
Hannah Walgrave ◽  
Sriram Balusu ◽  
Elke Vanden Eynden ◽  
Sarah Snoeck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Memory Decline ◽  
Human Neural Stem Cells ◽  
Neurogenic Niche

SummaryAdult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimer’s disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic niche in vivo and in human neural stem cells in vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.

scholarly journals A role for Lin28a in aging-associated decline of adult hippocampal neurogenesis

2022 ◽  
Author(s):  
Zhechun Hu ◽  
Jiao Ma ◽  
Huimin Yue ◽  
Xiaofang Li ◽  
Chao Wang ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Rna Binding ◽  
Functional Integration ◽  
Neural Progenitor ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Pattern Separation ◽  
Neurogenic Niche ◽  
Newborn Neurons

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein Lin28a remained existent in neural progenitor cells and granule neurons in the adult hippocampus, and decreased with aging. Loss of Lin28a inhibited the responsiveness of neural progenitor cells to niche Wnt agonist and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that Lin28a regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis as well as related cognitive functions.

scholarly journals Identifying biological pathways that underlie primordial short stature using network analysis

2014 ◽  
Vol 52 (3) ◽  
pp. 333-344 ◽  
Author(s):  
Dan Hanson ◽  
Adam Stevens ◽  
Philip G Murray ◽  
Graeme C M Black ◽  
Peter E Clayton
Keyword(s):  
Molecular Mechanisms ◽  
Growth Failure ◽  
Mrna Splicing ◽  
Hek293 Cells ◽  
Growth Disorders ◽  
Biological Functions ◽  
Altered Expression ◽  
Signalling Molecules ◽  
Cellular Pathways ◽  
Exon 11

Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M ‘interactome’, to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.

scholarly journals The Divergent Orphan Nuclear Receptor ODR-7 Regulates Olfactory Neuron Gene Expression via Multiple Mechanisms in Caenorhabditis elegans

Genetics ◽  
2003 ◽  
Vol 165 (4) ◽  
pp. 1779-1791
Author(s):  
Marc E Colosimo ◽  
Susan Tran ◽  
Piali Sengupta
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Receptor Gene ◽  
Biological Processes ◽  
Orphan Nuclear Receptor ◽  
Olfactory Neurons ◽  
C Elegans

Abstract Nuclear receptors regulate numerous critical biological processes. The C. elegans genome is predicted to encode ∼270 nuclear receptors of which >250 are unique to nematodes. ODR-7 is the only member of this large divergent family whose functions have been defined genetically. ODR-7 is expressed in the AWA olfactory neurons and specifies AWA sensory identity by promoting the expression of AWA-specific signaling genes and repressing the expression of an AWC-specific olfactory receptor gene. To elucidate the molecular mechanisms of action of a divergent nuclear receptor, we have identified residues and domains required for different aspects of ODR-7 function in vivo. ODR-7 utilizes an unexpected diversity of mechanisms to regulate the expression of different sets of target genes. Moreover, these mechanisms are distinct in normal and heterologous cellular contexts. The odr-7 ortholog in the closely related nematode C. briggsae can fully substitute for all ODR-7-mediated functions, indicating conservation of function across 25–120 million years of divergence.

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