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1.
PLoS Genet ; 17(11): e1009588, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34752452

RESUMO

Sex differences in gene expression are widespread in the liver, where many autosomal factors act in tandem with growth hormone signaling to regulate individual variability of sex differences in liver metabolism and disease. Here, we compare hepatic transcriptomic and epigenetic profiles of mouse strains C57BL/6J and CAST/EiJ, representing two subspecies separated by 0.5-1 million years of evolution, to elucidate the actions of genetic factors regulating liver sex differences. We identify 144 protein coding genes and 78 lncRNAs showing strain-conserved sex bias; many have gene ontologies relevant to liver function, are more highly liver-specific and show greater sex bias, and are more proximally regulated than genes whose sex bias is strain-dependent. The strain-conserved genes include key growth hormone-dependent transcriptional regulators of liver sex bias; however, three other transcription factors, Trim24, Tox, and Zfp809, lose their sex-biased expression in CAST/EiJ mouse liver. To elucidate the observed strain specificities in expression, we characterized the strain-dependence of sex-biased chromatin opening and enhancer marks at cis regulatory elements (CREs) within expression quantitative trait loci (eQTL) regulating liver sex-biased genes. Strikingly, 208 of 286 eQTLs with strain-specific, sex-differential effects on expression were associated with a complete gain, loss, or reversal of the sex differences in expression between strains. Moreover, 166 of the 286 eQTLs were linked to the strain-dependent gain or loss of localized sex-biased CREs. Remarkably, a subset of these CREs apparently lacked strain-specific genetic variants yet showed coordinated, strain-dependent sex-biased epigenetic regulation. Thus, we directly link hundreds of strain-specific genetic variants to the high variability in CRE activity and expression of sex-biased genes and uncover underlying genetically-determined epigenetic states controlling liver sex bias in genetically diverse mouse populations.


Assuntos
Regulação da Expressão Gênica , Variação Genética , Fígado/metabolismo , Sequências Reguladoras de Ácido Nucleico , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Locos de Características Quantitativas
2.
Epigenetics Chromatin ; 13(1): 30, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680543

RESUMO

Several thousand sex-differential distal enhancers have been identified in mouse liver; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization and chromatin interactions are unknown. To address these issues, we first characterized 1847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were primarily distal to sex-biased genes but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors, and were sometimes found in TADs without sex-biased genes. A substantial subset of sex-biased cohesin-non-CTCF binding sites, but not sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer-promoter interactions are common. Intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer-promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers. Furthermore, sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. These studies elucidate how 3D genome organization impacts sex-biased gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.


Assuntos
Cromatina/metabolismo , Genoma , Fígado/metabolismo , Sexo , Animais , Fator de Ligação a CCCTC/química , Fator de Ligação a CCCTC/metabolismo , Proteínas de Ciclo Celular/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Elementos Facilitadores Genéticos , Feminino , Masculino , Camundongos , Coesinas
3.
Elife ; 72018 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-29757144

RESUMO

CTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present and validate a computational method to predict cohesin-and-CTCF binding sites that form intra-TAD DNA loops. The intra-TAD loop anchors identified are structurally indistinguishable from TAD anchors regarding binding partners, sequence conservation, and resistance to cohesin knockdown; further, the intra-TAD loops retain key functional features of TADs, including chromatin contact insulation, blockage of repressive histone mark spread, and ubiquity across tissues. We propose that intra-TAD loops form by the same loop extrusion mechanism as the larger TAD loops, and that their shorter length enables finer regulatory control in restricting enhancer-promoter interactions, which enables selective, high-level expression of gene targets of super-enhancers and genes located within repressive nuclear compartments. These findings elucidate the role of intra-TAD cohesin-and-CTCF binding in nuclear organization associated with widespread insulation of distal enhancer activity.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , DNA/metabolismo , Expressão Gênica , Fígado/metabolismo , Animais , Sítios de Ligação , Simulação por Computador , Feminino , Masculino , Camundongos , Ligação Proteica , Coesinas
4.
Cell Rep ; 21(11): 3317-3328, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29241556

RESUMO

Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver dysfunction and low-grade inflammation during the development of diet-induced metabolic syndrome. We validated these model findings with additional experiments on mouse liver sections. In total, we present an integrative systems biology study of diet-induced hepatic insulin resistance that uncovered molecular features promoting the development and maintenance of metabolic disease.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hepatócitos/metabolismo , Fígado/metabolismo , Metaboloma/genética , Obesidade/genética , Transcriptoma , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Apoptose/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Hepatócitos/patologia , Hepatócitos/ultraestrutura , Insulina/metabolismo , Resistência à Insulina , Fígado/fisiopatologia , Fígado/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Mapeamento de Interação de Proteínas
5.
Proc Natl Acad Sci U S A ; 114(47): E10122-E10131, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29109290

RESUMO

In organisms from insects to vertebrates, Toll-like receptors (TLRs) are primary pathogen detectors that activate downstream pathways, specifically those that direct expression of innate immune effector genes. TLRs also have roles in development in many species. The sea anemone Nematostella vectensis is a useful cnidarian model to study the origins of TLR signaling because its genome encodes a single TLR and homologs of many downstream signaling components, including the NF-κB pathway. We have characterized the single N. vectensis TLR (Nv-TLR) and demonstrated that it can activate canonical NF-κB signaling in human cells. Furthermore, we show that the intracellular Toll/IL-1 receptor (TIR) domain of Nv-TLR can interact with the human TLR adapter proteins MAL and MYD88. We demonstrate that the coral pathogen Vibrio coralliilyticus causes a rapidly lethal disease in N. vectensis and that heat-inactivated V. coralliilyticus and bacterial flagellin can activate a reconstituted Nv-TLR-to-NF-κB pathway in human cells. By immunostaining of anemones, we show that Nv-TLR is expressed in a subset of cnidocytes and that many of these Nv-TLR-expressing cells also express Nv-NF-κB. Additionally, the nematosome, which is a Nematostella-specific multicellular structure, expresses Nv-TLR and many innate immune pathway homologs and can engulf V. coralliilyticus Morpholino knockdown indicates that Nv-TLR also has an essential role during early embryonic development. Our characterization of this primitive TLR and identification of a bacterial pathogen for N. vectensis reveal ancient TLR functions and provide a model for studying the molecular basis of cnidarian disease and immunity.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/imunologia , NF-kappa B/imunologia , Anêmonas-do-Mar/imunologia , Receptores Toll-Like/imunologia , Animais , Linhagem Celular , Galinhas , Embrião não Mamífero , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/microbiologia , Flagelina/farmacologia , Células HEK293 , Temperatura Alta , Humanos , Imunidade Inata , Morfolinos/genética , Morfolinos/metabolismo , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/imunologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , NF-kappa B/genética , Ligação Proteica , Anêmonas-do-Mar/genética , Anêmonas-do-Mar/crescimento & desenvolvimento , Anêmonas-do-Mar/microbiologia , Transdução de Sinais , Receptores Toll-Like/antagonistas & inibidores , Receptores Toll-Like/genética , Vibrio/patogenicidade , Vibrio/fisiologia
6.
Sci Rep ; 7(1): 174, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28282965

RESUMO

Diet plays a crucial role in shaping human health and disease. Diets promoting obesity and insulin resistance can lead to severe metabolic diseases, while calorie-restricted (CR) diets can improve health and extend lifespan. In this work, we fed mice either a chow diet (CD), a 16 week high-fat diet (HFD), or a CR diet to compare and contrast the effects of these diets on mouse liver biology. We collected transcriptomic and epigenomic datasets from these mice using RNA-Seq and DNase-Seq. We found that both CR and HFD induce extensive transcriptional changes, in some cases altering the same genes in the same direction. We used our epigenomic data to infer transcriptional regulatory proteins bound near these genes that likely influence their expression levels. In particular, we found evidence for critical roles played by PPARα and RXRα. We used ChIP-Seq to profile the binding locations for these factors in HFD and CR livers. We found extensive binding of PPARα near genes involved in glycolysis/gluconeogenesis and uncovered a role for this factor in regulating anaerobic glycolysis. Overall, we generated extensive transcriptional and epigenomic datasets from livers of mice fed these diets and uncovered new functions and gene targets for PPARα.


Assuntos
Restrição Calórica/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Fígado/química , PPAR alfa/genética , Anaerobiose , Animais , Epigênese Genética , Regulação da Expressão Gênica , Glicólise , Masculino , Camundongos , Estado Nutricional , Análise de Sequência de DNA , Análise de Sequência de RNA
7.
Retin Cases Brief Rep ; 11(1): 30-33, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26866434

RESUMO

PURPOSE: To describe the novel use of a chorioretinal biopsy technique to confirm the microbiological diagnosis of endogenous Escherichia coli (E. coli) endophthalmitis, when other investigations have been proven nondiagnostic. METHODS: Case report of an 82-year-old white man with endogenous endophthalmitis without a clearly identifiable source of infection. RESULTS: After systemic cultures and multiple aqueous and vitreous samples were unable to identify a causative organism, chorioretinal biopsy of a subretinal abscess was used to confirm the microbiological diagnosis. This ensured appropriate ophthalmic and systemic treatment of infection. CONCLUSION: Endogenous E. coli endophthalmitis is a rare and aggressive condition usually seen in patients with insulin-dependent diabetes with concurrent urinary tract infection. This case demonstrates chorioretinal biopsy to be a viable and effective method of establishing a firm microbiological diagnosis in cases of culture-negative endophthalmitis.


Assuntos
Endoftalmite/microbiologia , Infecções por Escherichia coli/diagnóstico , Escherichia coli/isolamento & purificação , Infecções Oculares Bacterianas/microbiologia , Idoso de 80 Anos ou mais , Biópsia , Corioide/microbiologia , Humanos , Masculino , Retina/microbiologia
9.
Cell Rep ; 14(2): 310-9, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26748710

RESUMO

MicroRNAs (miRNAs) regulate diverse biological processes by repressing mRNAs, but their modest effects on direct targets, together with their participation in larger regulatory networks, make it challenging to delineate miRNA-mediated effects. Here, we describe an approach to characterizing miRNA-regulatory networks by systematically profiling transcriptional, post-transcriptional and epigenetic activity in a pair of isogenic murine fibroblast cell lines with and without Dicer expression. By RNA sequencing (RNA-seq) and CLIP (crosslinking followed by immunoprecipitation) sequencing (CLIP-seq), we found that most of the changes induced by global miRNA loss occur at the level of transcription. We then introduced a network modeling approach that integrated these data with epigenetic data to identify specific miRNA-regulated transcription factors that explain the impact of miRNA perturbation on gene expression. In total, we demonstrate that combining multiple genome-wide datasets spanning diverse regulatory modes enables accurate delineation of the downstream miRNA-regulated transcriptional network and establishes a model for studying similar networks in other systems.


Assuntos
Código das Histonas/genética , MicroRNAs/genética , Fatores de Transcrição/genética , Redes Reguladoras de Genes , Humanos , MicroRNAs/metabolismo
10.
Proc Natl Acad Sci U S A ; 110(6): 2354-9, 2013 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-23341638

RESUMO

The earliest stages of Huntington disease are marked by changes in gene expression that are caused in an indirect and poorly understood manner by polyglutamine expansions in the huntingtin (HTT) protein. To explore the hypothesis that DNA methylation may be altered in cells expressing mutated HTT, we use reduced representation bisulfite sequencing (RRBS) to map sites of DNA methylation in cells carrying either wild-type or mutant HTT. We find that a large fraction of the genes that change in expression in the presence of mutant huntingtin demonstrate significant changes in DNA methylation. Regions with low CpG content, which have previously been shown to undergo methylation changes in response to neuronal activity, are disproportionately affected. On the basis of the sequence of regions that change in methylation, we identify AP-1 and SOX2 as transcriptional regulators associated with DNA methylation changes, and we confirm these hypotheses using genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq). Our findings suggest new mechanisms for the effects of polyglutamine-expanded HTT. These results also raise important questions about the potential effects of changes in DNA methylation on neurogenesis and cognitive decline in patients with Huntington disease.


Assuntos
Metilação de DNA , Proteínas Mutantes/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Animais , Linhagem Celular , Imunoprecipitação da Cromatina , Ilhas de CpG , Modelos Animais de Doenças , Expressão Gênica , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/metabolismo , Camundongos , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição AP-1/metabolismo
11.
Indian J Ophthalmol ; 61(12): 763-5, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24413827

RESUMO

A 67-year-old former gold miner with rheumatoid arthritis, treated with steroids and methotrexate, presented to eye casualty with a painful right eye. Examination revealed an anterior uveitis and despite an initial response to topical steroids, the intraocular inflammation worsened with anterior and posterior uveitis development. Re-examination showed a white mass in the peripheral nasal retina initially suspected of being active Toxoplasmosis infection and anti-toxoplasmosis treatment commenced. After improvement and tapering of this treatment, the intraocular inflammation reoccurred. Cytopathological examination of a pars plana vitrectomy obtained vitreous sample that showed a non-diagnostic non-infectious chronic vitritis. The vitreoretinal surgeons elected to do a direct biopsy of the white subretinal mass in the peripheral nasal area. This revealed, quite unexpectedly, an abscess containing pigmented phaeohyphomycosis fungi. This case report documents the multidisciplinary approach that assisted in clinching a final diagnosis and the role of sub-retinal biopsy in this unprecedented scenario.


Assuntos
Abscesso/complicações , Artrite Reumatoide/complicações , Endoftalmite/complicações , Infecções Oculares Fúngicas/complicações , Feoifomicose/complicações , Retina/microbiologia , Tuberculose Pulmonar/complicações , Abscesso/diagnóstico , Idoso , Artrite Reumatoide/diagnóstico , Biópsia , Diagnóstico Diferencial , Endoftalmite/diagnóstico , Infecções Oculares Fúngicas/diagnóstico , Humanos , Masculino , Feoifomicose/diagnóstico , Retina/patologia , Tuberculose Pulmonar/diagnóstico
12.
Horm Behav ; 61(5): 725-33, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22498693

RESUMO

While the survival value of paternal care is well understood, little is known about its physiological basis. Here we investigate the neuroendocrine contributions to paternal care in the monogamous cichlid, Amatitlania nigrofasciata. We first explored the dynamic range of paternal care in three experimental groups: biparental males (control fathers housed with their mate), single fathers (mate removed), or lone males (mate and offspring removed). We found that control males gradually increase paternal care over time, whereas single fathers increased care immediately after mate removal. Males with offspring present had lower levels of circulating 11-ketotestosterone (11-KT) yet still maintained aggressive displays toward brood predators. To determine what brain regions may contribute to paternal care, we quantified induction of the immediate early gene c-Fos, and found that single fathers have more c-Fos induction in the forebrain area Vv (putative lateral septum homologue), but not in the central pallium (area Dc). While overall preoptic area c-Fos induction was similar between groups, we found that parvocellular preoptic isotocin (IST) neurons in single fathers showed increased c-Fos induction, suggesting IST may facilitate the increase of paternal care after mate removal. To functionally test the role of IST in regulating paternal care, we treated biparental males with an IST receptor antagonist, which blocked paternal care. Our results indicate that isotocin plays a significant role in promoting paternal care, and more broadly suggest that the convergent evolution of paternal care across vertebrates may have recruited similar neuroendocrine mechanisms.


Assuntos
Ciclídeos/fisiologia , Ocitocina/análogos & derivados , Comportamento Paterno/efeitos dos fármacos , Agressão/efeitos dos fármacos , Agressão/fisiologia , Androgênios/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Feminino , Masculino , Preferência de Acasalamento Animal/fisiologia , Comportamento de Nidação/fisiologia , Ocitócicos/farmacologia , Ocitocina/farmacologia , Ocitocina/fisiologia , Ligação do Par , Comportamento Paterno/fisiologia
13.
Br J Ophthalmol ; 96(3): 329-31, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21856690

RESUMO

AIM: To demonstrate a novel surgical technique for the accurate diagnosis of iris lesions using a minimally invasive aspiration cannula. METHOD: 12 consecutive patients underwent biopsy of iris lesions at the Ocular Oncology Service, Royal Hallamshire Hospital, Sheffield, UK. Samples were obtained using a novel technique called trans-corneal fine cannula aspiration. This comprised a 25-gauge, Rycroft cannula aspiration technique performed by a single surgeon and samples transferred into alcohol-based tissue fixative. A specialist ophthalmic histopathologist performed a histological analysis of the samples. RESULTS: On average, the size of the specimens obtained in theatre ranged from 1 mm to 1.5 mm (maximum dimensions). This sample size allowed an unequivocal histological diagnosis in all 12 cases. In this study, 10 patients were diagnosed as having iris melanoma, one patient with metastatic adenocarcinoma and one patient with pigmented adenoma. CONCLUSIONS: This simple iris tumour biopsy technique provides sufficiently large sample sizes to obtain a firm histological diagnosis in 100% of cases performed so far. The sample sizes permitted not only morphological interpretation but also ancillary investigations such as immunohistochemistry.


Assuntos
Adenocarcinoma/patologia , Adenoma/patologia , Drenagem/métodos , Neoplasias da Íris/patologia , Melanoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina/métodos , Cateterismo/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Adulto Jovem
14.
Exp Dermatol ; 20(9): 703-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21507066

RESUMO

Oestrogen deprivation is one of the major factors responsible for many age-related processes, including poor wound healing in women. Previously, it has been shown that oestrogens have a modulatory effect in different wound-healing models. Therefore, in this study, the effect of selective oestrogen receptor (ER) agonists (PPT - ER-α agonist, DPN - ER-ß agonist) on excisional and incisional wound-healing models was compared in ovariectomised rats in vivo as well as on human dermal fibroblasts (HDF) and human umbilical endothelial cells (HUVEC) in vitro. In the in vivo study, 4 months after either ovariectomy or sham ovariectomy, Sprague-Dawley rats were randomly divided into four groups and subjected to two incisional and excisional wounds: (i) control - sham operated, vehicle-treated; (ii) ovariectomised, vehicle-treated; (iii) ovariectomised, PPT treated; (iv) ovariectomised, DPN treated. In the in vitro study, HDFs and HUVECs were used. After treatment with ER agonists, cells were processed for immunocytochemistry and gelatin zymography. Our study shows that stimulation of ER-α leads to the differentiation of fibroblasts into myofibroblasts both in vivo and in vitro. On the other hand, the formation of extracellular matrix was more prominent, and wound tensile strength (TS) was increased when ER-ß was stimulated. In contrast, stimulation of ER-α led to a more prominent increase in the expression of MMP-2 and decrease in wound TS. New information is presented in this investigation concerning oestrogen replacement therapy (ERT) in different wound-healing models. This study demonstrates that the ERT should be both wound and receptor-type specific.


Assuntos
Receptor alfa de Estrogênio/agonistas , Receptor beta de Estrogênio/agonistas , Matriz Extracelular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/lesões , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Fibroblastos/citologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Técnicas In Vitro , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , Nitrilas/farmacologia , Ovariectomia , Fenóis/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Pele/fisiopatologia , Resistência à Tração/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
15.
Gen Comp Endocrinol ; 171(1): 64-74, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21185292

RESUMO

Progesterone and its nuclear receptor are critical in modulating reproductive physiology and behavior in female and male vertebrates. Whiptail lizards (genus Cnemidophorus) are an excellent model system in which to study the evolution of sexual behavior, as both the ancestral and descendent species exist. Male-typical sexual behavior is mediated by progesterone in both the ancestral species and the descendant all-female species, although the molecular characterization and distribution of the progesterone receptor protein throughout the reptilian brain is not well understood. To better understand the gene targets and ligand binding properties of the progesterone receptor in whiptails, we cloned the promoter and coding sequence of the progesterone receptor and analyzed the predicted protein structure. We next determined the distribution of the progesterone receptor protein and mRNA throughout the brain of Cnemidophorus inornatus and Cnemidophorus uniparens by immunohistochemistry and in situ hybridization. We found the progesterone receptor to be present in many brain regions known to regulate social behavior and processing of stimulus salience across many vertebrates, including the ventral tegmental area, amygdala, nucleus accumbens and several hypothalamic nuclei. Additionally, we quantified immunoreactive cells in the preoptic area and ventromedial hypothalamus in females of both species and males of the ancestral species. We found differences between both species and across ovarian states. Our results significantly extend our understanding of progesterone modulation in the reptilian brain and support the important role of the nuclear progesterone receptor in modulating sexual behavior in reptiles and across vertebrates.


Assuntos
Encéfalo/metabolismo , Lagartos/metabolismo , Receptores de Progesterona/metabolismo , Animais , Feminino , Imuno-Histoquímica , Hibridização In Situ , Lagartos/genética , Masculino , Filogenia , Estrutura Secundária de Proteína , Receptores de Progesterona/química , Receptores de Progesterona/genética
16.
Brain Behav Evol ; 76(3-4): 211-25, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21099197

RESUMO

Dopamine is an evolutionarily ancient neurotransmitter that plays an essential role in mediating behavior. In vertebrates, dopamine is central to the mesolimbic reward system, a neural network concerned with the valuation of stimulus salience, and to the nigrostriatal motor system and hypothalamic nuclei involved in the regulation of locomotion and social behavior. In amphibians, dopaminergic neurons have been mapped out in several species, yet the distribution of dopaminoreceptive cells is unknown. The túngara frog, Physalaemus pustulosus, is an excellent model system for the study of neural mechanisms by which valuations of stimuli salience and social decisions are made, especially in the context of mate choice. In order to better understand where dopamine acts to regulate social decisions in this species, we have determined the distribution of putative dopaminergic cells (using tyrosine hydroxylase immunohistochemistry) and cells receptive to dopaminergic signaling (using DARPP-32 immunohistochemistry) throughout the brain of P. pustulosus. The distribution of dopaminergic cells was comparable to other anurans. DARPP-32 immunoreactivity was identified in key brain regions known to modulate social behavior in other vertebrates including the proposed anuran homologues of the mammalian amygdalar complex, nucleus accumbens, hippocampus, striatum, preoptic area, anterior hypothalamus, ventromedial hypothalamus, and ventral tegmental area/substantia nigra pars compacta. Due to its widespread distribution, DARPP-32 likely also plays many roles in non-limbic brain regions that mediate non-social information processing. These results significantly extend our understanding of the distribution of the dopaminergic system in the anuran brain and beyond.


Assuntos
Anuros/fisiologia , Mapeamento Encefálico , Encéfalo/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Dopamina/metabolismo , Animais , Encéfalo/anatomia & histologia , Feminino , Imuno-Histoquímica , Vias Neurais/anatomia & histologia , Vias Neurais/metabolismo , Técnicas de Rastreamento Neuroanatômico , Distribuição Tecidual , Tirosina 3-Mono-Oxigenase/metabolismo
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