Na+/H+ exchanger 1 deficiency alters gene expression in mouse brain

2004 ◽  
Vol 18 (3) ◽  
pp. 331-339 ◽  
Author(s):  
Dan Zhou ◽  
Jin Xue ◽  
Orit Gavrialov ◽  
Gabriel G. Haddad
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Global Gene Expression ◽  
Brain Regions ◽  
Inhibitory Effect ◽  
Null Mouse ◽  
Null Mutation ◽  
Null Mutant ◽  
Altered Expression ◽  
Null Mutant Mice

Na+/H+ exchanger 1 (NHE1) is well known to function as a major regulator of intracellular pH (pHi). It is activated by low pHi and exchanges extracellular Na+ for intracellular H+ to maintain cellular homeostasis. Despite the fact that we now have evidence suggesting other roles for NHE1, there has been no comprehensive study investigating its role as a signaling molecule. Toward this aim, we used in this study NHE1 null mutant mice and cDNA microarrays to investigate the effects of NHE1 on global gene expression in various regions of the brain, e.g., cortex, hippocampus, brain stem-diencephalon, and cerebellum. We found that a total of 35 to 79 genes were up- or downregulated in each brain region, with the majority being downregulated. The effect of NHE1 null mutation on gene expression is region specific, and only 11 genes were changed in all brain regions studied. Further analysis of the cis-regulatory regions of downregulated genes revealed that transcription suppressors, BCL6 and E4BP4, were probable candidates that mediated the inhibitory effect of NHE1 null mutation. One of the genes, MCT-13, was not only downregulated in the NHE1 null mutant brain but also in tissue cultures treated with an NHE1 inhibitor. We conclude that 1) a relatively small number of genes were altered in the NHE1 null mouse brain; 2) the effects of NHE1 null mutation on gene expression are region specific; and 3) several genes implicated in neurodegeneration have altered expression, potentially offering a molecular explanation for the phenotype of the NHE1 null mouse.

scholarly journals Contrasting Roles of Ang II and ACEA in the Regulation of IL10 and IL1β Gene Expression in Primary SHR Astroglial Cultures

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 3012
Author(s):  
Dhanush Haspula ◽  
Michelle A. Clark
Keyword(s):  
Gene Expression ◽  
Wistar Rats ◽  
Gene Signature ◽  
Brain Regions ◽  
Inhibitory Effect ◽  
Ang Ii ◽  
Cannabinoid Type 1 Receptor ◽  
Il10 Gene ◽  
Cerebellar Astrocytes

Angiotensin (Ang) II is well-known to have potent pro-oxidant and pro-inflammatory effects in the brain. Extensive crosstalk between the primary Ang II receptor, Ang type 1 receptor (AT1R), and the cannabinoid type 1 receptor (CB1R) has been demonstrated by various groups in the last decade. Since activation of glial CB1R has been demonstrated to play a key role in the resolution of inflammatory states, we investigated the role of Ang II (100 nM) and/or ACEA (10 nM), a potent CB1R-specific agonist in the regulation of inflammatory markers in astrocytes from spontaneously hypertensive rats (SHR) and Wistar rats. Astrocytes were cultured from brainstems and cerebellums of SHR and Wistar rats and assayed for IL1β and IL10 gene expression and secreted fraction, in treated and non-treated cells, by employing qPCR and ELISA, respectively. mRNA expression of both IL10 and IL1β were significantly elevated in untreated brainstem and cerebellar astrocytes isolated from SHR when compared to Wistar astrocytes. No changes were observed in the secreted fraction. While ACEA-treatment resulted in a significant increase in IL10 gene expression in Wistar brainstem astrocytes (Log2FC ≥ 1, p < 0.05), its effect in SHR brainstem astrocytes was diminished. Ang II treatment resulted in a strong inhibitory effect on IL10 gene expression in astrocytes from both brain regions of SHR and Wistar rats (Log2FC ≤ −1, p < 0.05), and an increase in IL1β gene expression in brainstem astrocytes from both strains (Log2FC ≥ 1, p < 0.05). Co-treatment of Ang II and ACEA resulted in neutralization of Ang II-mediated effect in Wistar brainstem and cerebellar astrocytes, but not SHR astrocytes. Neither Ang II nor ACEA resulted in any significant changes in IL10 or IL1β secreted proteins. These data suggest that Ang II and ACEA have opposing roles in the regulation of inflammatory gene signature in astrocytes isolated from SHR and Wistar rats. This however does not translate into changes in their secreted fractions.

scholarly journals Dynamical consequences of regional heterogeneity in the brain’s transcriptional landscape

2020 ◽  
Author(s):  
Gustavo Deco ◽  
Kevin Aquino ◽  
Aurina Arnatkevičiūtė ◽  
Stuart Oldham ◽  
Kristina Sabaroedin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Global Gene Expression ◽  
Brain Regions ◽  
Biophysical Model ◽  
Neuronal Dynamics ◽  
Regional Heterogeneity ◽  
Magnetic Resonance Imaging Mri

AbstractBrain regions vary in their molecular and cellular composition, but how this heterogeneity shapes neuronal dynamics is unclear. Here, we investigate the dynamical consequences of regional heterogeneity using a biophysical model of whole-brain functional magnetic resonance imaging (MRI) dynamics in humans. We show that models in which transcriptional variations in excitatory and inhibitory receptor (E:I) gene expression constrain regional heterogeneity more accurately reproduce the spatiotemporal structure of empirical functional connectivity estimates than do models constrained by global gene expression profiles and MRI-derived estimates of myeloarchitecture. We further show that regional heterogeneity is essential for yielding both ignition-like dynamics, which are thought to support conscious processing, and a wide variance of regional activity timescales, which supports a broad dynamical range. We thus identify a key role for E:I heterogeneity in generating complex neuronal dynamics and demonstrate the viability of using transcriptional data to constrain models of large-scale brain function.

scholarly journals Stimulation of later functions of the yeast meiotic protein kinase Ime2p by the IDS2 gene product.

1995 ◽  
Vol 15 (10) ◽  
pp. 5279-5287 ◽  
Author(s):  
R A Sia ◽  
A P Mitchell
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Functional Relationship ◽  
Null Mutation ◽  
Null Mutant ◽  
Meiotic Gene ◽  
Late Genes ◽  
Gal1 Promoter ◽  
New Gene ◽  
Stimulation Of

Ime2p is a protein kinase that is expressed only during meiosis in Saccharomyces cerevisiae. Ime2p stimulates early, middle, and late meiotic gene expression and down-regulates expression of IME1, which specifies an activator of early meiotic genes that acts independently of Ime2p. We have identified a new gene, IDS2 (for IME2-dependent signaling), which has a functional relationship to Ime2p. An ids2 null mutation delays down-regulation of IME1 and expression of middle and late meiotic genes. In an ime1 null mutant that express IME2 from the GAL1 promoter (ime1 delta PGAL1-IME2 mutant), early meiotic gene expression depends only upon Ime2p. In such strains, Ids2p is dispensable for expression of the early genes HOP1 and SPO13 but is essential for expression of the middle and late genes SPS1, SPS2, and SPS100. Ids2p is also essential for the autoregulatory pathway through which Ime2p activates its own expression via the IME2 upstream activation sequences (UAS). An PGAL1-IME2 derivative that produces a truncated Ime2p (lacking its C-terminal 174 residues) permits IME2 UAS activation in the absence of Ids2p. This observation suggests that Ids2p acts upstream of Ime2p or that Ids2p and Ime2p act in independent, convergent pathways to stimulate IME2 UAS activity. Accumulation of epitope-tagged Ids2p derivatives is greatest in growing cells and declines during meiosis. We propose that Ids2p acts indirectly to modify Ime2p activity, thus permitting Ime2p to carry out later meiotic functions.

scholarly journals Null Mutation in Transforming Growth Factor β1 Disrupts Ovarian Function and Causes Oocyte Incompetence and Early Embryo Arrest

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 835-845 ◽  
Author(s):  
Wendy V. Ingman ◽  
Rebecca L. Robker ◽  
Karen Woittiez ◽  
Sarah A. Robertson
Keyword(s):  
Transforming Growth Factor ◽  
Ovarian Function ◽  
Mutant Mice ◽  
Reproductive Capacity ◽  
Null Mutation ◽  
Null Mutant ◽  
Critical Determinant ◽  
Serum Progesterone ◽  
Null Mutant Mice

TGFβ1 is implicated in regulation of ovarian function and the events of early pregnancy. We have investigated the effect of null mutation in the Tgfβ1 gene on reproductive function in female mice. The reproductive capacity of TGFβ1 null mutant females was severely impaired, leading to almost complete infertility. Onset of sexual maturity was delayed, after which ovarian function was disrupted, with extended ovarian cycles, irregular ovulation, and a 40% reduction in oocytes ovulated. Serum FSH and estrogen content were normal, but TGFβ1 null mutant mice failed to display the characteristic proestrus surge in circulating LH. Ovarian hyperstimulation with exogenous gonadotropins elicited normal ovulation rates in TGFβ1 null mutant mice. After mating with wild-type stud males, serum progesterone content was reduced by 75% associated with altered ovarian expression of mRNAs encoding steroidogenic enzymes 3β-hydroxysteroid dehydrogenase-1 and P450 17 α-hydroxylase/C17–20-lyase. Embryos recovered from TGFβ1 null mutant females were developmentally arrested in the morula stage and rarely progressed to blastocysts. Attempts to rescue embryos by exogenous progesterone administration and in vitro culture were unsuccessful, and in vitro fertilization and culture experiments demonstrated that impaired development is unlikely to result from lack of maternal tract TGFβ1. We conclude that embryo arrest is due to developmental incompetence in oocytes developed in a TGFβ1-deficient follicular environment. This study demonstrates that TGFβ1 is a critical determinant of normal ovarian function, operating through regulation of LH activity and generation of oocytes competent for embryonic development and successful initiation of pregnancy.

scholarly journals Integrative Analysis of Global Gene Expression Identifies Opposite Patterns of Reactive Astrogliosis in Aged Human Prefrontal Cortex

2018 ◽  
Author(s):  
César Payán-Gómez ◽  
Diego Rodríguez ◽  
Diana Amador-Munoz ◽  
Sandra Ramirez
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Brain Aging ◽  
Global Gene Expression ◽  
Brain Regions ◽  
Molecular Signature ◽  
Analytic Approximation ◽  
Shh Pathway ◽  
Transcriptomic Signature ◽  
First Time

Prefrontal cortex (PFC) is one of the brain regions with more prominent changes in human aging. The molecular processes related to the aging cognitive decline and mood changes are not completely understood. In order to improve our knowledge, we integrated transcriptomic data of four studies of human PFC from old people -58-80 years old- compared with young people -20-40 years old- using a meta-analytic approximation combined with molecular signature analysis. We identified 1816 differentially expressed genes -561 up-regulated and 1256 down-regulated. Pathway analysis revealed down-regulation of synaptic genes with conservation of gene expression of other neuronal regions. Additionally, we identified up-regulation of markers of astrogliosis with transcriptomic signature compatible with A1 neurotoxic astrocytes and A2 neuroprotective astrocytes. Response to interferon is related to A1 astrocytes and the A2 phenotype is mediated in aging by activation of SHH pathway and up-regulation of metallothioneins I and genes of the family EZR -ezrin, radixin, and moesin-. The main conclusions of our study are the confirmation that in aged PFC there is a global dysfunction of the synapses and we reported for the first time opposite phenotypes of astrogliosis because of brain aging.

Analysis of global gene expression at seven brain regions of patients with schizophrenia

2020 ◽  
Vol 223 ◽  
pp. 119-127
Author(s):  
Paweł Karpiński ◽  
Jerzy Samochowiec ◽  
Maria M. Sąsiadek ◽  
Łukasz Łaczmański ◽  
Błażej Misiak
Keyword(s):  
Gene Expression ◽  
Global Gene Expression ◽  
Brain Regions

scholarly journals Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Monica Sonzogni ◽  
Peipei Zhai ◽  
Edwin J. Mientjes ◽  
Geeske M. van Woerden ◽  
Ype Elgersma
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Brain Development ◽  
Mouse Brain ◽  
Angelman Syndrome ◽  
Neurodevelopmental Disorder ◽  
Brain Regions ◽  
Critical Function ◽  
Behavioral Phenotypes ◽  
Mouse Brain Development

Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. Methods Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. Results We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. Limitations Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. Conclusions Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21.

scholarly journals The Sinorhizobium meliloti SyrM Regulon: Effects on Global Gene Expression Are Mediated bysyrAandnodD3

2015 ◽  
Vol 197 (10) ◽  
pp. 1792-1806 ◽  
Author(s):  
Melanie J. Barnett ◽  
Sharon R. Long
Keyword(s):  
Gene Expression ◽  
Sinorhizobium Meliloti ◽  
Developmental Process ◽  
Global Gene Expression ◽  
Subsequent Increase ◽  
Altered Expression ◽  
Content Type ◽  
Regulatory Circuit ◽  
Regulatory Circuits ◽  
Exogenous Compounds

ABSTRACTInSinorhizobium meliloti, three NodD transcriptional regulators activate bacterial nodulation (nod) gene expression. NodD1 and NodD2 require plant compounds to activatenodgenes. The NodD3 protein does not require exogenous compounds to activatenodgene expression; instead, another transcriptional regulator, SyrM, activatesnodD3expression. In addition, NodD3 can activatesyrMexpression. SyrM also activates expression of another gene,syrA, which when overexpressed causes a dramatic increase in exopolysaccharide production. In a previous study, we identified more than 200 genes with altered expression in a strain overexpressingnodD3. In this work, we define the transcriptomes of strains overexpressingsyrMorsyrA. ThesyrM,nodD3, andsyrAoverexpression transcriptomes share similar gene expression changes; analyses imply thatnodD3andsyrAare the only targets directly activated by SyrM. We propose that most of the gene expression changes observed whennodD3is overexpressed are due to NodD3 activation ofsyrMexpression, which in turn stimulates SyrM activation ofsyrAexpression. The subsequent increase in SyrA abundance results in broad changes in gene expression, most likely mediated by the ChvI-ExoS-ExoR regulatory circuit.IMPORTANCESymbioses with bacteria are prevalent across the animal and plant kingdoms. Our system of study, the rhizobium-legume symbiosis (Sinorhizobium melilotiandMedicagospp.), involves specific host-microbe signaling, differentiation in both partners, and metabolic exchange of bacterial fixed nitrogen for host photosynthate. During this complex developmental process, both bacteria and plants undergo profound changes in gene expression. TheS. melilotiSyrM-NodD3-SyrA and ChvI-ExoS-ExoR regulatory circuits affect gene expression and are important for optimal symbiosis. In this study, we defined the transcriptomes ofS. melilotioverexpressing SyrM or SyrA. In addition to identifying new targets of the SyrM-NodD3-SyrA regulatory circuit, our work further suggests how it is linked to the ChvI-ExoS-ExoR regulatory circuit.

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