Revealing genomic changes responsible for cannabinoid receptor loss in parrots: mechanism and functional effects

In vertebrates, an ancient duplication in the genes for cannabinoid receptors (CNRs) allowed the evolution of specialised endocannabinoid receptors expressed in the brain (CNR1) and the periphery (CNR2). While dominantly conserved throughout vertebrate phylogeny, our comparative genomic analysis suggests that certain taxa may have lost either the CNR1 regulator of neural processes or, more frequently, the CNR2 involved in immune regulation. Focussing on conspicuous CNR2 pseudogenization in parrots (Psittaciformes), a diversified crown lineage of cognitively-advanced birds, we highlight possible functional effects of such a loss. Parrots appear to have lost the CNR2 gene at at least two separate occasions due to chromosomal rearrangement. Using gene expression data from the brain and periphery of birds with experimentally-induced sterile inflammation, we compare CNR and inflammatory marker (interleukin 1 beta, IL1B) expression patterns in CNR2-deficient parrots (represented by the budgerigar, Melopsittacus undulatus and five other parrot species) with CNR2-intact passerines (represented by the zebra finch, Taeniopygia guttata). Though no significant changes in CNR expression were observed in either parrots or passerines during inflammation of the brain or periphery, we detected a significant up-regulation of IL1B expression in the brain after stimulation with lipopolysaccharide (LPS) only in parrots. As our analysis failed to show evidence for selection on altered CNR1 functionality in parrots, compared to other birds, CNR1 is unlikely to be involved in compensation for CNR2 loss in modulation of the neuroimmune interaction. Thus, our results provide evidence for the functional importance of CNR2 pseudogenization for regulation of neuroinflammation.

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Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22158051 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8051

Author(s):

Rodrigo Teodoro ◽

Daniel Gündel ◽

Winnie Deuther-Conrad ◽

Lea Ueberham ◽

Magali Toussaint ◽

...

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Biological Evaluation ◽

Emission Tomography ◽

Tailored Therapy ◽

Positron Emission ◽

Cannabinoid Receptor Type 2 ◽

Attractive Therapeutic Target ◽

The Brain

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

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Enhancer Trapping and Annotation in Zebrafish Mediated with Sleeping Beauty, piggyBac and Tol2 Transposons

Genes ◽

10.3390/genes9120630 ◽

2018 ◽

Vol 9 (12) ◽

pp. 630 ◽

Cited By ~ 1

Author(s):

Dan Shen ◽

Songlei Xue ◽

Shuheng Chan ◽

Yatong Sang ◽

Saisai Wang ◽

...

Keyword(s):

Expression Profiles ◽

Expression Patterns ◽

Genomic Analysis ◽

Sleeping Beauty ◽

Comparative Genomic Analysis ◽

Regulatory Function ◽

Comparative Genomic ◽

Gfp Expression ◽

Enhancer Trapping ◽

Multiple Expression

Although transposon-mediated enhancer trapping (ET) is successfully applied in diverse models, the efficiency of various transposon systems varies significantly, and little information is available regarding efficiency of enhancer trapping by various transposons in zebrafish. Most potential enhancers (Ens) still lack evidence of actual En activity. Here, we compared the differences in ET efficiency between sleeping beauty (SB), piggyBac (PB) and Tol2 transposons. Tol2 represented the highest germline transfer efficiencies at 55.56% (NF0 = 165), followed by SB (38.36%, NF0 = 151) and PB (32.65%, NF0 = 149). ET lines generated by the Tol2 transposon tended to produce offspring with a single expression pattern per line, while PB and SB tended to generate embryos with multiple expression patterns. In our tests, 10 putative Ens (En1–10) were identified by splinkerette PCR and comparative genomic analysis. Combining the GFP expression profiles and mRNA expression patterns revealed that En1 and En2 may be involved in regulation of the expression of dlx1a and dlx2a, while En6 may be involved in regulation of the expression of line TK4 transgene and rps26, and En7 may be involved in the regulation of the expression of wnt1 and wnt10b. Most identified Ens were found to be transcribed in zebrafish embryos, and their regulatory function may involve eRNAs.

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Abstinence from chronic methylphenidate exposure modifies cannabinoid receptor 1 levels in the brain in a dose-dependent manner

Current Pharmaceutical Design ◽

10.2174/1381612827666210127120411 ◽

2021 ◽

Vol 27 ◽

Author(s):

Carly Connor ◽

John Hamilton ◽

Lisa Robison ◽

Michael Hadjiargyrou ◽

David Komatsu ◽

...

Keyword(s):

Basal Ganglia ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

High Dose ◽

Dependent Manner ◽

Water Control ◽

Cannabinoid Receptor 1 ◽

The Brain ◽

Abstinence Period

Introduction: Methylphenidate (MP) is a widely used psychostimulant prescribed for Attention Deficit Hyperactivity Disorder, and is also used illicitly by healthy individuals. Chronic exposure to MP has been shown to affect physiology, behavior, and neurochemistry. Methods: The present study examined its effect on the endocannabinoid system. Adolescent rats had daily oral access to either water (control), low dose MP (4/10 mg/kg), or high dose MP (30/60 mg/kg). After 13 weeks of exposure, half of the rats in each group were euthanized, however the remaining rats underwent a four-week long abstinence period. Cannabinoid receptor 1 binding (CB1) was measured with in vitro autoradiography using [3H] SR141716A. Results: Rats who underwent a 4-week abstinence period after exposure to chronic HD MP showed increased binding compared to rats with no abstinence period in several cortical and basal ganglia regions of the brain. In contrast to this, rats who underwent a 4-week abstinence period after exposure to chronic LD MP showed lower binding compared to rats with no abstinence period in mainly the basal ganglia regions and in the hindlimb region of the somatosensory cortex. Following 4 weeks of drug abstinence, rats who were previously given HD MP showed higher [ 3H] SR141716A binding than rats given LD MP in many of the cortical and basal ganglia regions examined. These results highlight biphasic effects of MP treatment on cannabinoid receptor levels. Abstinence from HD MP seemed to increase CB1 receptor levels while abstinence from LD MP seemed to decrease CB1 levels. Conclusion: Given the prolific expression of cannabinoid receptors throughout the brain, many types of behaviors may be affected as a result of MP abstinence. Further research will be needed to help identify these behavioral changes.

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Endocannabinoid System in Hepatic Glucose Metabolism, Fatty Liver Disease, and Cirrhosis

International Journal of Molecular Sciences ◽

10.3390/ijms20102516 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2516 ◽

Cited By ~ 10

Author(s):

Ivonne Bazwinsky-Wutschke ◽

Alexander Zipprich ◽

Faramarz Dehghani

Keyword(s):

Insulin Resistance ◽

Portal Hypertension ◽

Liver Disease ◽

Glucose Metabolism ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Expression Patterns ◽

Endocannabinoid System ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose

There is growing evidence that glucose metabolism in the liver is in part under the control of the endocannabinoid system (ECS) which is also supported by its presence in this organ. The ECS consists of its cannabinoid receptors (CBRs) and enzymes that are responsible for endocannabinoid production and metabolism. ECS is known to be differentially influenced by the hepatic glucose metabolism and insulin resistance, e.g., cannabinoid receptor type 1(CB1) antagonist can improve the glucose tolerance and insulin resistance. Interestingly, our own study shows that expression patterns of CBRs are influenced by the light/dark cycle, which is of significant physiological and clinical interest. The ECS system is highly upregulated during chronic liver disease and a growing number of studies suggest a mechanistic and therapeutic impact of ECS on the development of liver fibrosis, especially putting its receptors into focus. An opposing effect of the CBRs was exerted via the CB1 or CB2 receptor stimulation. An activation of CB1 promoted fibrogenesis, while CB2 activation improved antifibrogenic responses. However, underlying mechanisms are not yet clear. In the context of liver diseases, the ECS is considered as a possible mediator, which seems to be involved in the synthesis of fibrotic tissue, increase of intrahepatic vascular resistance and subsequently development of portal hypertension. Portal hypertension is the main event that leads to complications of the disease. The main complication is the development of variceal bleeding and ascites, which have prognostic relevance for the patients. The present review summarizes the current understanding and impact of the ECS on glucose metabolism in the liver, in association with the development of liver cirrhosis and hemodynamics in cirrhosis and its complication, to give perspectives for development of new therapeutic strategies.

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Gene Duplication and Gain in the Trematode Atriophallophorus Winterbourni Contributes to Adaptation to Parasitism

Genome Biology and Evolution ◽

10.1093/gbe/evab010 ◽

2021 ◽

Author(s):

Natalia Zajac ◽

Stefan Zoller ◽

Katri Seppälä ◽

David Moi ◽

Christophe Dessimoz ◽

...

Keyword(s):

De Novo ◽

Genomic Analysis ◽

Enrichment Analysis ◽

Gene Families ◽

Comparative Genomic ◽

Genomic Changes ◽

Go Enrichment ◽

Duplication Events ◽

Parasitic Lifestyle ◽

Host Parasite

Abstract Gene duplications and novel genes have been shown to play a major role in helminth adaptation to a parasitic lifestyle because they provide the novelty necessary for adaptation to a changing environment, such as living in multiple hosts. Here we present the de novo sequenced and annotated genome of the parasitic trematode Atriophallophorus winterbourni and its comparative genomic analysis to other major parasitic trematodes. First, we reconstructed the species phylogeny, and dated the split of A. winterbourni from the Opisthorchiata suborder to approximately 237.4 MYA (± 120.4 MY). We then addressed the question of which expanded gene families and gained genes are potentially involved in adaptation to parasitism. To do this, we used Hierarchical Orthologous Groups to reconstruct three ancestral genomes on the phylogeny leading to A. winterbourni and performed a GO enrichment analysis of the gene composition of each ancestral genome, allowing us to characterize the subsequent genomic changes. Out of the 11,499 genes in the A. winterbourni genome, as much as 24% have arisen through duplication events since the speciation of A. winterbourni from the Opisthorchiata, and as much as 31.9% appear to be novel, i.e. newly acquired. We found 13 gene families in A. winterbourni to have had more than 10 genes arising through these recent duplications; all of which have functions potentially relating to host behavioural manipulation, host tissue penetration, and hiding from host immunity through antigen presentation. We identified several families with genes evolving under positive selection. Our results provide a valuable resource for future studies on the genomic basis of adaptation to parasitism and point to specific candidate genes putatively involved in antagonistic host-parasite adaptation.

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High Levels of β-Amyloid, Tau, and Phospho-Tau in Red Blood Cells as Biomarkers of Neuropathology in Senescence-Accelerated Mouse

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/5030475 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 9

Author(s):

Rebecca Piccarducci ◽

Deborah Pietrobono ◽

Carolina Pellegrini ◽

Simona Daniele ◽

Matteo Fornai ◽

...

Keyword(s):

Red Blood Cells ◽

Blood Cells ◽

Inflammatory Marker ◽

Interleukin 1 ◽

Biochemical Alterations ◽

Amyloid A ◽

Accumulation Kinetics ◽

Samp8 Mice ◽

The Brain ◽

Senescence Accelerated Mouse

Alzheimer’s Disease (AD) is the most common Neurodegenerative Disease (ND), primarily characterised by neuroinflammation, neuronal plaques of β-amyloid (Aβ), and neurofibrillary tangles of hyperphosphorylated tau. α-Synuclein (α-syn) and its heteroaggregates with Aβ and tau have been recently included among the neuropathological elements of NDs. These pathological traits are not restricted to the brain, but they reach peripheral fluids as well. In this sense, Red Blood Cells (RBCs) are emerging as a good model to investigate the biochemical alterations of aging and NDs. Herein, the levels of homo- and heteroaggregates of ND-related proteins were analysed at different stages of disease progression. In particular, a validated animal model of AD, the SAMP8 (Senescence-Accelerated Mouse-Prone) and its control strain SAMR1 (Senescence-Accelerated Mouse-Resistant) were used in parallel experiments. The levels of the aforementioned proteins and of the inflammatory marker interleukin-1β (IL-1β) were examined in both brain and RBCs of SAMP8 and SAMR1 at 6 and 8 months. Brain Aβ, tau, and phospho-tau (p-tau) were higher in SAMP8 mice than in control mice and increased with AD progression. Similar accumulation kinetics were found in RBCs, even if slower. By contrast, α-syn and its heterocomplexes (α-syn-Aβ and α-syn-tau) displayed different accumulation kinetics between brain tissue and RBCs. Both brain and peripheral IL-1β levels were higher in SAMP8 mice, but increased sooner in RBCs, suggesting that inflammation might initiate at a peripheral level before affecting the brain. In conclusion, these results confirm RBCs as a valuable model for monitoring neurodegeneration, suggesting peripheral Aβ, tau, and p-tau as potential early biomarkers of AD.

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The Genomes of Sheeppox and Goatpox Viruses

Journal of Virology ◽

10.1128/jvi.76.12.6054-6061.2002 ◽

2002 ◽

Vol 76 (12) ◽

pp. 6054-6061 ◽

Cited By ~ 163

Author(s):

E. R. Tulman ◽

C. L. Afonso ◽

Z. Lu ◽

L. Zsak ◽

J.-H. Sur ◽

...

Keyword(s):

Host Range ◽

Genomic Sequence ◽

Indian Subcontinent ◽

Interleukin 1 ◽

Central Africa ◽

Myxoma Virus ◽

Nucleotide Identity ◽

Comparative Genomic ◽

Genomic Changes ◽

Ankyrin Repeat Proteins

ABSTRACT Sheeppox virus (SPPV) and goatpox virus (GTPV), members of the Capripoxvirus genus of the Poxviridae, are etiologic agents of important diseases of sheep and goats in northern and central Africa, southwest and central Asia, and the Indian subcontinent. Here we report the genomic sequence and comparative analysis of five SPPV and GTPV isolates, including three pathogenic field isolates and two attenuated vaccine viruses. SPPV and GTPV genomes are approximately 150 kbp and are strikingly similar to each other, exhibiting 96% nucleotide identity over their entire length. Wild-type genomes share at least 147 putative genes, including conserved poxvirus replicative and structural genes and genes likely involved in virulence and host range. SPPV and GTPV genomes are very similar to that of lumpy skin disease virus (LSDV), sharing 97% nucleotide identity. All SPPV and GTPV genes are present in LSDV. Notably in both SPPV and GTPV genomes, nine LSDV genes with likely virulence and host range functions are disrupted, including a gene unique to LSDV (LSDV132) and genes similar to those coding for interleukin-1 receptor, myxoma virus M003.2 and M004.1 genes (two copies each), and vaccinia virus F11L, N2L, and K7L genes. The absence of these genes in SPPV and GTPV suggests a significant role for them in the bovine host range. SPPV and GTPV genomes contain specific nucleotide differences, suggesting they are phylogenetically distinct. Relatively few genomic changes in SPPV and GTPV vaccine viruses account for viral attenuation, because they contain 71 and 7 genomic changes compared to their respective field strains. Notable genetic changes include mutation or disruption of genes with predicted functions involving virulence and host range, including two ankyrin repeat proteins in SPPV and three kelch-like proteins in GTPV. These comparative genomic data indicate the close genetic relationship among capripoxviruses, and they suggest that SPPV and GTPV are distinct and likely derived from an LSDV-like ancestor.

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Cannabinoid Receptors CB1 and CB2 Modulate the Electroretinographic Waves in Vervet Monkeys

Neural Plasticity ◽

10.1155/2016/1253245 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Joseph Bouskila ◽

Vanessa Harrar ◽

Pasha Javadi ◽

Amy Beierschmitt ◽

Roberta Palmour ◽

...

Keyword(s):

Wave Amplitude ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Expression Patterns ◽

Amacrine Cells ◽

Retinal Function ◽

Receptor Type ◽

Vervet Monkeys ◽

Full Field

The expression patterns of the cannabinoid receptor type 1 (CB1R) and the cannabinoid receptor type 2 (CB2R) are well documented in rodents and primates. In vervet monkeys, CB1R is present in the retinal neurons (photoreceptors, horizontal cells, bipolar cells, amacrine cells, and ganglion cells) and CB2R is exclusively found in the retinal glia (Müller cells). However, the role of these cannabinoid receptors in normal primate retinal function remains elusive. Using full-field electroretinography in adult vervet monkeys, we recorded changes in neural activity following the blockade of CB1R and CB2R by the intravitreal administration of their antagonists (AM251 and AM630, resp.) in photopic and scotopic conditions. Our results show that AM251 increases the photopic a-wave amplitude at high flash intensities, whereas AM630 increases the amplitude of both the photopic a- and b-waves. In scotopic conditions, both blockers increased the b-wave amplitude but did not change the a-wave amplitude. These findings suggest an important role of CB1R and CB2R in primate retinal function.

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Comparative genomic analysis of the tricarboxylic acid cycle members in four Solanaceae vegetable crops and expression pattern analysis in Solanum tuberosum

BMC Genomics ◽

10.1186/s12864-021-08109-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yongming Liu ◽

Jingtao Qu ◽

Ziwen Shi ◽

Peng Zhang ◽

Maozhi Ren

Keyword(s):

Solanum Tuberosum ◽

Tricarboxylic Acid Cycle ◽

Expression Patterns ◽

Solanum Melongena ◽

Genomic Analysis ◽

Tca Cycle ◽

Tissue Expression ◽

Tricarboxylic Acid ◽

Comparative Genomic ◽

Vegetable Crops

Abstract Background The tricarboxylic acid (TCA) cycle is crucial for energy supply in animal, plant, and microbial cells. It is not only the main pathway of carbohydrate catabolism but also the final pathway of lipid and protein catabolism. Some TCA genes have been found to play important roles in the growth and development of tomato and potato, but no comprehensive study of TCA cycle genes in Solanaceae crops has been reported. Results In this study, we analyzed TCA cycle genes in four important Solanaceae vegetable crops (potato (Solanum tuberosum), tomato (Solanum lycopersicum), eggplant (Solanum melongena), and pepper (Capsicum annuum)) based on comparative genomics. The four Solanaceae crops had a total of 180 TCA cycle genes: 43 in potato, 44 in tomato, 40 in eggplant, and 53 in pepper. Phylogenetic analysis, collinearity analysis, and tissue expression patterns revealed the conservation of and differences in TCA cycle genes between the four Solanaceae crops and found that there were unique subgroup members in Solanaceae crops that were independent of Arabidopsis genes. The expression analysis of potato TCA cycle genes showed that (1) they were widely expressed in various tissues, and some transcripts like Soltu.DM.01G003320.1(SCoAL) and Soltu.DM.04G021520.1 (SDH) mainly accumulate in vegetative organs, and some transcripts such as Soltu.DM.12G005620.3 (SDH) and Soltu.DM.02G007400.4 (MDH) are preferentially expressed in reproductive organs; (2) several transcripts can be significantly induced by hormones, such as Soltu.DM.08G023870.2 (IDH) and Soltu.DM.06G029290.1 (SDH) under ABA treatment, and Soltu.DM.07G021850.2 (CSY) and Soltu.DM.09G026740.1 (MDH) under BAP treatment, and Soltu.DM.02G000940.1 (IDH) and Soltu.DM.01G031350.4 (MDH) under GA treatment; (3) Soltu.DM.11G024650.1 (SDH) can be upregulated by the three disease resistance inducers including Phytophthora infestans, acibenzolar-S-methyl (BTH), and DL-β-amino-n-butyric acid (BABA); and (4) the levels of Soltu.DM.01G045790.1 (MDH), Soltu.DM.01G028520.3 (CSY), and Soltu.DM.12G028700.1 (CSY) can be activated by both NaCl and mannitol. The subcellular localization results of three potato citrate synthases showed that Soltu.DM.01G028520.3 was localized in mitochondria, while Soltu.DM.12G028700.1 and Soltu.DM.07G021850.1 were localized in the cytoplasm. Conclusions This study provides a scientific foundation for the comprehensive understanding and functional studies of TCA cycle genes in Solanaceae crops and reveals their potential roles in potato growth, development, and stress response.

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Genome-wide characterization, evolutionary analysis of WRKY genes in Cucurbitaceae species and assessment of its roles in resisting to powdery mildew disease

10.1101/350892 ◽

2018 ◽

Author(s):

Zigao Jiao ◽

Jianlei Sun ◽

Chongqi Wang ◽

Yumei Dong ◽

Shouhua Xiao ◽

...

Keyword(s):

Powdery Mildew ◽

Expression Profiles ◽

Expression Patterns ◽

Genomic Analysis ◽

Large Family ◽

Comparative Genomic ◽

Evolutionary Analysis ◽

Multiple Sequence ◽

Wide Range ◽

Wrky Proteins

AbstractThe WRKY proteins constitute a large family of transcription factors that have been known to play a wide range of regulatory roles in multiple biological processes. Over the past few years, many reports have focused on analysis of evolution and biological function of WRKY genes at the whole genome level in different plant species. However, little information is known about WRKY genes in melon (Cucumis melo L.). In the present study, a total of 56 putative WRKY genes were identified in melon, which were randomly distributed on their respective chromosomes. A multiple sequence alignment and phylogenetic analysis using melon, cucumber and watermelon predicted WRKY domains indicated that melon WRKY proteins could be classified into three main groups (I-III). Our analysis indicated that no recent duplication events of WRKY genes were detected in melon, and strong purifying selection was observed among the 85 orthologous pairs of Cucurbitaceae species. Expression profiles of CmWRKY derived from RNA-seq data and quantitative RT-PCR (qRT-PCR) analyses showed distinct expression patterns in various tissues, and the expression of 16 CmWRKY were altered following powdery mildew infection in melon. Besides, we also found that a total of 24 WRKY genes were co-expressed with 11 VQ family genes in melon. Our comparative genomic analysis provides a foundation for future functional dissection and understanding the evolution of WRKY genes in cucurbitaceae species, and will promote powdery mildew resistance study in melon.

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