scholarly journals Region-specific Foxp2 deletions in cortex, striatum or cerebellum cannot explain vocalization deficits observed in spontaneous global knockouts

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Bastiaan H. A. Urbanus ◽  
Saša Peter ◽  
Simon E. Fisher ◽  
Chris I. De Zeeuw
Keyword(s):  
Gene Expression ◽  
Language Comprehension ◽  
Motor Performance ◽  
Broadband Noise ◽  
Conditional Knockout ◽  
Ultrasonic Vocalizations ◽  
Rare Mutations ◽  
Key Sites ◽  
The Impact ◽  
The Brain

AbstractFOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension. Disruptions of the murine orthologue Foxp2 in mouse pups have been shown to interfere with production of ultrasonic vocalizations (USVs). However, it remains unclear which structures are responsible for these deficits. Here, we show that conditional knockout mice with selective Foxp2 deletions targeting the cerebral cortex, striatum or cerebellum, three key sites of motor control with robust neural gene expression, do not recapture the profile of pup USV deficits observed in mice with global disruptions of this gene. Moreover, we observed that global Foxp2 knockout pups show substantive reductions in USV production as well as an overproduction of short broadband noise “clicks”, which was not present in the brain region-specific knockouts. These data indicate that deficits of Foxp2 expression in the cortex, striatum or cerebellum cannot solely explain the disrupted vocalization behaviours in global Foxp2 knockouts. Our findings raise the possibility that the impact of Foxp2 disruption on USV is mediated at least in part by effects of this gene on the anatomical prerequisites for vocalizing.

Tet2 Loss Accelerates The Myeloproliferative Neoplasm (MPN) Phenotype Of Jak2V617F Knockin Mice But Is Insufficient To Cause Leukemic Transformation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4095-4095
Author(s):  
Edwin Chen ◽  
Lawrence J Breyfogle ◽  
Rebekka K. Schneider ◽  
Luke Poveromo ◽  
Ross L. Levine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Conditional Knockout ◽  
The Other ◽  
Myelogenous Leukemia ◽  
Leukemic Transformation ◽  
The Impact

Abstract TET2 mutations are early somatic events in the pathogenesis of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN) and are one of the most common genetic lesions found in these diseases. In MPN, TET2 mutations are enriched within more advanced disease phenotypes such as myelofibrosis and leukemic transformation and often co-occur with the JAK2V617F mutation, which is present in the majority of MPN patients. We have developed and characterized a Jak2V617F conditional knockin mouse (Jak2VF/+), the phenotype of which closely recapitulates the features of human MPN. To determine the impact of Tet2 loss on Jak2V617F-mediated MPN, we crossed Tet2 conditional knockout mice with Jak2VF/+ knockin and Vav-Cre transgenic mice and backcrossed the compound mutant animals. We then characterized the effects of heterozygous and homozygous loss of Tet2 on the phenotype of Jak2VF/+ mice. We assessed peripheral blood counts, histopathology, hematopoietic differentiation using flow cytometry, colony formation and re-plating capacity. We also evaluated the effects of Tet2 loss on the transcriptome of the HSC compartment using gene expression microarrays and on HSC function using competitive bone marrow transplantation assays. Similar to Jak2VF/+/VavCre+ mice, Tet2+/-/Jak2VF/+/VavCre+ and Tet2-/-/Jak2VF/+/VavCre+ mice develop leukocytosis, elevated hematocrits (HCT) and thrombocytosis. Tet2-/-/Jak2VF/+/VavCre+ mice demonstrate enhanced leukocytosis and splenomegaly compared to the other groups. All groups demonstrate myeloid expansion, erythroid hyperplasia and megakaryocytic abnormalities consistent with MPN in the bone marrow and spleen, while more prominent myeloid expansion and megakaryocytic morphological abnormalities are observed in Tet2-/-/Jak2VF/+/VavCre+ mice as compared to the other groups. Notably, we do not see the development of acute myelogenous leukemia (AML) in Tet2-/-/Jak2VF/+/VavCre+ mice at 6 months. We see enhanced expansion of lineagelowSca1+cKithigh (LSK) cells (enriched for HSC) most prominently in the spleens of Tet2+/-/Jak2VF/+/VavCre+ and Tet2-/-/Jak2VF/+/VavCre+ mice as compared to Jak2VF/+/VavCre+ mice. In colony forming assays, we find that Tet2-/-/Jak2VF/+/VavCre+ LSK cells have enhanced re-plating activity compared to Jak2VF/+/VavCre+ LSK cells and that Tet2-/-/Jak2VF/+/VavCre+ LSK cells form more colonies that Tet2-/-/Jak2+/+/VavCre+ cells. Gene expression analysis demonstrates enrichment of a HSC self-renewal signature inTet2-/-/Jak2VF/+/VavCre+ LSK cells. Concordant with this, we find that Tet2-/-/Jak2VF/+/VavCre+ LSK cells have enhanced competitive repopulation at 16 weeks as compared to Jak2VF/+/VavCre+ and Tet2+/-/Jak2VF/+/VavCre+ LSK cells. In aggregate these findings demonstrate that Tet2 loss promotes disease progression in MPN but is insufficient to drive full leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Gut-derived Metabolites Influence Neurodevelopmental Gene Expression and Wnt Signalling Events in a Germ-free Zebrafish Model

2022 ◽  
Author(s):  
Terry Van Raay ◽  
Victoria Rea ◽  
Ian Bell
Keyword(s):  
Gene Expression ◽  
Neural Development ◽  
Morphological Changes ◽  
Wnt Signalling ◽  
Gene Ontology Analysis ◽  
Rna Seq ◽  
Zebrafish Model ◽  
Germ Free ◽  
The Impact ◽  
The Brain

Abstract Background : Small molecule metabolites produced by the microbiome are known to be neuroactive and are capable of directly impacting the brain and central nervous system, yet there is little data on the contribution of these metabolites to the earliest stages of neural development and neural gene expression. Here, we explore the impact of deriving zebrafish embryos in the absence of microbes on early neural development as well as investigate whether any potential changes can be rescued with treatment of metabolites derived from the zebrafish gut microbiota. Results : Overall, we did not observe any gross morphological changes between treatments but did observe a significant decrease in neural gene expression in embryos raised germ-free, which was rescued with the addition of zebrafish metabolites. Specifically, we identified 354 genes significantly down regulated in germ-free embryos compared to conventionally raised embryos via RNA-Seq analysis. Of these, 42 were rescued with a single treatment of zebrafish gut-derived metabolites to germ-free embryos. Gene ontology analysis revealed that these genes are involved in prominent neurodevelopmental pathways including transcriptional regulation and Wnt signalling. Consistent with the ontology analysis, we found alterations in the development of Wnt dependent events which was rescued in the germ-free embryos treated with metabolites. Conclusions : These findings demonstrate that gut-derived metabolites are in part responsible for regulating critical signalling pathways in the brain, especially during neural development.

scholarly journals Gut-derived metabolites influence neurodevelopmental gene expression and Wnt signalling events in a germ-free zebrafish model

2021 ◽  
Author(s):  
Victoria Rea ◽  
Ian Bell ◽  
Terence J Van Raay
Keyword(s):  
Gene Expression ◽  
Neural Development ◽  
Morphological Changes ◽  
Wnt Signalling ◽  
Gene Ontology Analysis ◽  
Rna Seq ◽  
Zebrafish Model ◽  
Germ Free ◽  
The Impact ◽  
The Brain

Small molecule metabolites produced by the microbiome are known to be neuroactive and are capable of directly impacting the brain and central nervous system, yet there is little data on the contribution of these metabolites to the earliest stages of neural development and neural gene expression. Here, we explore the impact of rearing zebrafish embryos in the absence of microbes on early neural development as well as investigate whether any potential changes can be rescued with treatment of metabolites derived from the zebrafish gut microbiota. Overall, we did not observe any gross morphological changes between treatments but did observe a significant decrease in neural gene expression in embryos raised germ-free, which was rescued with the addition of zebrafish metabolites. Specifically, we identified 361 genes significantly down regulated in GF embryos compared to conventionally raised embryos via RNA-Seq analysis. Of these, 42 were rescued with the treatment of zebrafish gut-derived metabolites to GF embryos. Gene ontology analysis revealed that these genes are involved in prominent neurodevelopmental pathways including transcriptional regulation and Wnt signalling. Consistent with the ontology analysis, we found alterations in the development of Wnt dependent events which is rescued in the GF embryos treated with metabolites.

Fto-modulated lipid niche regulates adult neurogenesis through modulating adenosine metabolism

2020 ◽  
Vol 29 (16) ◽  
pp. 2775-2787
Author(s):  
Hui Gao ◽  
Xuejun Cheng ◽  
Junchen Chen ◽  
Chai Ji ◽  
Hongfeng Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adult Neurogenesis ◽  
Neuronal Development ◽  
Local Environment ◽  
Conditional Knockout ◽  
Neurogenic Niche ◽  
Altered Gene Expression ◽  
Altered Gene ◽  
Newborn Neurons ◽  
The Brain

Abstract Adult neurogenesis is regulated by diverse factors including the local environment, i.e. the neurogenic niche. However, whether the lipid in the brain regulates adult neurogenesis and related mechanisms remains largely unknown. In the present study, we found that lipid accumulates in the brain during postnatal neuronal development. Conditional knockout of Fto (cKO) in lipid not only reduced the level of lipid in the brain but also impaired the learning and memory of mice. In addition, Fto deficiency in lipid did not affect the proliferation of adult neural stem cells (aNSCs), but it did inhibit adult neurogenesis by inducing cell apoptosis. Mechanistically, specific deleting Fto in lipid altered gene expression and increased adenosine secretion of adipocytes. The treatment of adenosine promoted the apoptosis of newborn neurons. As a whole, these results reveal the important function of the lipid niche and its associated mechanism in regulating adult neurogenesis.

scholarly journals Brain α-Tocopherol Concentration and Stereoisomer Profile Alter Hippocampal Gene Expression in Weanling Mice

2020 ◽  
Vol 150 (12) ◽  
pp. 3075-3085 ◽  
Author(s):  
Justin S Rhodes ◽  
Catarina Rendeiro ◽  
Jonathan G Mun ◽  
Kristy Du ◽  
Pragya Thaman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin E ◽  
Transcription Regulation ◽  
Synapse Formation ◽  
Alpha Tocopherol ◽  
Tocopherol Concentration ◽  
Kinase C ◽  
The Impact ◽  
Protein Kinase C Zeta ◽  
The Brain

ABSTRACT Background Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood. Objectives The objective was to determine the impact of bio-potency–adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice. Methods Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams. Results A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz). Conclusions In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.

The Impact of Oxytocin Gene Knockout on Sexual Behavior and Gene Expression Related to Neuroendocrine Systems in the Brain of Female Mice

2016 ◽  
Vol 37 (5) ◽  
pp. 803-815 ◽  
Author(s):  
Josi Maria Zimmermann-Peruzatto ◽  
Virgínia Meneghini Lazzari ◽  
Grasiela Agnes ◽  
Roberta Oriques Becker ◽  
Ana Carolina de Moura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sexual Behavior ◽  
Gene Knockout ◽  
Female Mice ◽  
The Impact ◽  
The Brain ◽  
Neuroendocrine Systems

scholarly journals Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling

2021 ◽  
Vol 14 ◽  
Author(s):  
Darío García-Rodríguez ◽  
Alfredo Giménez-Cassina
Keyword(s):  
Gene Expression ◽  
Neuronal Excitability ◽  
Ketone Bodies ◽  
Biological Effects ◽  
Epileptic Seizures ◽  
Ketogenic Diets ◽  
Infantile Seizures ◽  
Neuronal Physiology ◽  
The Impact ◽  
The Brain

Ketone bodies are metabolites that replace glucose as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting, extenuating exercise, or pathological conditions such as diabetes. Beyond their role as an alternative fuel for the brain, the impact of ketone bodies on neuronal physiology has been highlighted by the use of the so-called “ketogenic diets,” which were proposed about a century ago to treat infantile seizures. These diets mimic fasting by reducing drastically the intake of carbohydrates and proteins and replacing them with fat, thus promoting ketogenesis. The fact that ketogenic diets have such a profound effect on epileptic seizures points to complex biological effects of ketone bodies in addition to their role as a source of ATP. In this review, we specifically focus on the ability of ketone bodies to regulate neuronal excitability and their effects on gene expression to respond to oxidative stress. Finally, we also discuss their capacity as signaling molecules in brain cells.

scholarly journals Intermittent Hypoxia Alters the Circadian Expression of Clock Genes in Mouse Brain and Liver

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1627
Author(s):  
Bala S. C. Koritala ◽  
Yin Yeng Lee ◽  
Shweta S. Bhadri ◽  
Laetitia S. Gaspar ◽  
Corinne Stanforth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Intermittent Hypoxia ◽  
Clock Genes ◽  
The United States ◽  
Circadian Expression ◽  
Polymerase Chain ◽  
States Experience ◽  
The Impact ◽  
The Brain

At least one-third of adults in the United States experience intermittent hypoxia (IH) due to health or living conditions. The majority of these adults suffer with sleep breathing conditions and associated circadian rhythm disorders. The impact of IH on the circadian clock is not well characterized. In the current study, we used an IH mouse model to understand the impact of IH on the circadian gene expression of the canonical clock genes in the central (the brain) and peripheral (the liver) tissues. Gene expression was measured using a Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). CircaCompare was used to evaluate the differential rhythmicity between normoxia and IH. Our observations suggested that the circadian clock in the liver was less sensitive to IH compared to the circadian clock in the brain.

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