RESUMO
Selection to increase body weight in poultry can hamper reproduction traits and compromise production efficiency. Thus, attention to reproduction traits is essential to improving the sustainability of breeding programs. Data from a domestic quail breeding program for meat production were used to estimate genetic parameters. We analyzed five traits: 4-week body weight, age at sexual maturity for males and females, cloacal gland area, female, and male reproductive organs weights. A multi-trait mixed model analysis with fixed effects of generation/hatch was performed, assuming environmental covariance equals zero for sex-limited traits. Heritability estimates range from low to moderate for male sexual maturity and cloacal gland area, and high for other traits. Intersexual genetic correlation for age at sexual maturity is positive, which can lead to correlated responses in the other sex. Reproductive organs weights are genetically correlated with body weight, but not significantly between sexes and nor with sexual maturity. Genetic correlations for the cloacal gland area were positive with body weight and negative with age at sexual maturity of males and females, demonstrating a potential use of this trait for selection with favorable outcomes in reproduction. The use of the cloacal gland area can be used in the same way as the scrotal circumference in mammals, improving female reproduction traits by selecting a trait recorded in males.
Assuntos
Peso Corporal , Codorniz , Maturidade Sexual , Animais , Masculino , Feminino , Maturidade Sexual/genética , Peso Corporal/genética , Codorniz/genética , Codorniz/fisiologia , Tamanho do Órgão/genética , CloacaRESUMO
The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.
Assuntos
Estudo de Associação Genômica Ampla , Cabeça , Neoplasias , Humanos , Cabeça/anatomia & histologia , Neoplasias/genética , Neoplasias/patologia , Feminino , Masculino , Polimorfismo de Nucleotídeo Único/genética , Variação Genética , Tamanho do Órgão/genética , Transdução de Sinais/genética , Adulto , Predisposição Genética para DoençaRESUMO
Our study was designed to examine the correlation between single nucleotide polymorphism (SNP) in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene, specifically focusing on rs27434, and plural tissue weight. We conducted this investigation using autopsy samples from the Japanese population. Blood samples were collected from 178 Japanese subjects who had undergone autopsies in Shimane Prefecture. Genomic DNA was subsequently extracted from these samples. SNP (rs27434, Gï¼A substitution) was analyzed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. In the present study, rs27434 exhibited a statistically significant association with brain weight (g) in both female and male individuals. Among males, rs27434 displayed significant relationships with liver weight (g), and body surface area (m2). In females, rs27434 was significantly related to the length of the appendix. Across both genders, individuals with GA and AA genotypes tended to exhibit higher levels in these respective measurements compared to those with the GG genotype. These results suggest that genetic variant of ERAP1 gene may influence the weight of the organs. To the best of our knowledge, this is the first study investigating the interaction between the association of rs27434 in the ERAP1 gene and data routinely measured at autopsy, such as tissue weight. However, conducting further investigations with larger population samples could provide more comprehensive insights to clarify this issue.
Assuntos
Aminopeptidases , Antígenos de Histocompatibilidade Menor , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aminopeptidases/genética , Povo Asiático/genética , Autopsia , Encéfalo/metabolismo , Genótipo , Japão , Fígado , Antígenos de Histocompatibilidade Menor/genética , Tamanho do Órgão/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoRESUMO
Organ size shapes plant architecture during rice (Oryza sativa) growth and development, affecting key factors influencing yield, such as plant height, leaf size, and seed size. Here, we report that the rice Enhancer of Zeste [E(z)] homolog SET DOMAIN GROUP 711 (OsSDG711) regulates organ size in rice. Knockout of OsSDG711 produced shorter plants with smaller leaves, thinner stems, and smaller grains. We demonstrate that OsSDG711 affects organ size by reducing cell length and width and increasing cell number in leaves, stems, and grains. The result of chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) using an antitrimethylation of histone H3 lysine 27 (H3K27me3) antibody showed that the levels of H3K27me3 associated with cytokinin oxidase/dehydrogenase genes (OsCKXs) were lower in the OsSDG711 knockout line Ossdg711. ChIP-qPCR assays indicated that OsSDG711 regulates the expression of OsCKX genes through H3K27me3 histone modification. Importantly, we show that OsSDG711 directly binds to the promoters of these OsCKX genes. Furthermore, we measured significantly lower cytokinin contents in Ossdg711 plants than in wild-type plants. Overall, our results reveal an epigenetic mechanism based on OsSDG711-mediated modulation of H3K27me3 levels to regulate the expression of genes involved in the cytokinin metabolism pathway and control organ development in rice. OsSDG711 may be an untapped epigenetic resource for ideal plant type improvement.
Assuntos
Histonas , Oryza , Histonas/genética , Histonas/metabolismo , Oryza/metabolismo , Tamanho do Órgão/genética , Domínios PR-SET , Metilação , Citocininas/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
BACKGROUND AND AIMS: Gigantism is a key component of the domestication syndrome, a suite of traits that differentiates crops from their wild relatives. Allometric gigantism is strongly marked in horticultural crops, causing disproportionate increases in the size of edible parts such as stems, leaves or fruits. Tomato (Solanum lycopersicum) has attracted attention as a model for fruit gigantism, and many genes have been described controlling this trait. However, the genetic basis of a corresponding increase in size of vegetative organs contributing to isometric gigantism has remained relatively unexplored. METHODS: Here, we identified a 0.4-Mb region on chromosome 7 in introgression lines (ILs) from the wild species Solanum pennellii in two different tomato genetic backgrounds (cv. 'M82' and cv. 'Micro-Tom') that controls vegetative and reproductive organ size in tomato. The locus, named ORGAN SIZE (ORG), was fine-mapped using genotype-by-sequencing. A survey of the literature revealed that ORG overlaps with previously mapped quantitative trait loci controlling tomato fruit weight during domestication. KEY RESULTS: Alleles from the wild species led to lower cell number in different organs, which was partially compensated by greater cell expansion in leaves, but not in fruits. The result was a proportional reduction in leaf, flower and fruit size in the ILs harbouring the alleles from the wild species. CONCLUSIONS: Our findings suggest that selection for large fruit during domestication also tends to select for increases in leaf size by influencing cell division. Since leaf size is relevant for both source-sink balance and crop adaptation to different environments, the discovery of ORG could allow fine-tuning of these parameters.
Assuntos
Gigantismo , Solanum lycopersicum , Solanum , Solanum lycopersicum/genética , Tamanho do Órgão/genética , Gigantismo/genética , Locos de Características Quantitativas/genética , Solanum/genética , Frutas/genéticaRESUMO
Ethylene-responsive factors (ERFs) have diverse functions in the regulation of various plant developmental processes. Here, we demonstrate the dual role of an Arabidopsis ERF gene, AtERF19, in regulating reproductive meristem activity and flower organ size through the regulation of genes involved in CLAVATA-WUSCHEL (CLV-WUS) and auxin signaling, respectively. We found that AtERF19 stimulated the formation of flower primordia and controlled the number of flowers produced by activating WUS and was negatively regulated by CLV3. 35S::AtERF19 expression resulted in significantly more flowers, whereas 35S::AtERF19 + SRDX dominant-negative mutants produced fewer flowers. In addition, AtERF19 also functioned to control flower organ size by promoting the division/expansion of the cells through activating Small Auxin Up RNA Gene 32 (SAUR32), which positively regulated MYB21/24 in the auxin signaling pathway. 35S::AtERF19 and 35S::SAUR32 resulted in similarly larger flowers, whereas 35S::AtERF19 + SRDX and 35S::SAUR32-RNAi mutants produced smaller flowers than the wild type. The functions of AtERF19 were confirmed by the production of similarly more and larger flowers in 35S::AtERF19 transgenic tobacco (Nicotiana benthamiana) and in transgenic Arabidopsis which ectopically expressed the orchid gene (Nicotiana benthamiana) PaERF19 than in wild-type plants. The finding that AtERF19 regulates genes involved in both CLV-WUS and auxin signaling during flower development significantly expands the current knowledge of the multifunctional evolution of ERF genes in plants. The results presented in this work indicate a dual role for the transcription factor AtERF19 in controlling the number of flowers produced and flower organ size through the regulation of genes involved in CLV-WUS and auxin signaling, respectively. Our findings expand the knowledge of the roles of ERF genes in the regulation of reproductive development.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/fisiologia , Proteínas de Arabidopsis/metabolismo , Meristema , Tamanho do Órgão/genética , Flores , Ácidos Indolacéticos , Regulação da Expressão Gênica de Plantas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The neurobiological underpinnings of action-related episodic memory and how enactment contributes to efficient memory encoding are not well understood. We examine whether individual differences in level (n = 338) and 5-year change (n = 248) in the ability to benefit from motor involvement during memory encoding are related to gray matter (GM) volume, white matter (WM) integrity, and dopamine-regulating genes in a population-based cohort (age range = 25-80 years). A latent profile analysis identified 2 groups with similar performance on verbal encoding but with marked differences in the ability to benefit from motor involvement during memory encoding. Impaired ability to benefit from enactment was paired with smaller HC, parahippocampal, and putamen volume along with lower WM microstructure in the fornix. Individuals with reduced ability to benefit from encoding enactment over 5 years were characterized by reduced HC and motor cortex GM volume along with reduced WM microstructure in several WM tracts. Moreover, the proportion of catechol-O-methyltransferase-Val-carriers differed significantly between classes identified from the latent-profile analysis. These results provide converging evidence that individuals with low or declining ability to benefit from motor involvement during memory encoding are characterized by low and reduced GM volume in regions critical for memory and motor functions along with altered WM microstructure.
Assuntos
Catecol O-Metiltransferase , Córtex Cerebral , Memória Episódica , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/fisiologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiologia , Estudos Transversais , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiologia , Hipocampo/diagnóstico por imagem , Hipocampo/fisiologia , Imageamento por Ressonância Magnética/métodos , Córtex Motor/diagnóstico por imagem , Córtex Motor/fisiologia , Tamanho do Órgão/genética , Tamanho do Órgão/fisiologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiologiaRESUMO
RNA-directed DNA methylation (RdDM) is an epigenetic process that directs silencing to specific genomic regions and loci. The biological functions of RdDM are not well studied in horticultural plants. Here, we isolated the ethyl methane-sulfonate-induced mutant reduced organ size (ros) producing small leaves, flowers, and fruits in woodland strawberry (Fragaria vesca) due to reduced cell numbers compared with that in the wild-type (WT). The candidate mutation causes a premature stop codon in FvH4_6g28780, which shares high similarity to Arabidopsis (Arabidopsis thaliana) Factor of DNA Methylation1 (FDM1) encoding an RdDM pathway component and was named FveFDM1. Consistently, the fvefdm1CR mutants generated by CRISPR/Cas9 also produced smaller organs. Overexpressing FveFDM1 in an Arabidopsis fdm1-1 fdm2-1 double mutant restored DNA methylation at the RdDM target loci. FveFDM1 acts in a protein complex with its homolog Involved in De Novo 2 (FveIDN2). Furthermore, whole-genome bisulfite sequencing revealed that DNA methylation, especially in the CHH context, was remarkably reduced throughout the genome in fvefdm1. Common and specific differentially expressed genes were identified in different tissues of fvefdm1 compared to in WT tissues. DNA methylation and expression levels of several gibberellic acid (GA) biosynthesis and cell cycle genes were validated. Moreover, the contents of GA and auxin were substantially reduced in the young leaves of fvefdm1 compared to in the WT. However, exogenous application of GA and auxin could not recover the organ size of fvefdm1. In addition, expression levels of FveFDM1, FveIDN2, Nuclear RNA Polymerase D1 (FveNRPD1), Domains Rearranged Methylase 2 (FveDRM2), and cell cycle genes were greatly induced by GA treatment. Overall, our work demonstrated the critical roles of FveFDM1 in plant growth and development via RdDM-mediated DNA methylation in horticultural crops.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Fragaria , Metilação de DNA/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Fragaria/genética , Fragaria/metabolismo , Proteínas de Arabidopsis/metabolismo , Tamanho do Órgão/genética , Regulação da Expressão Gênica de Plantas , RNA Interferente Pequeno/genética , DNA de Plantas/metabolismoRESUMO
Understanding the causes of the morphological diversity among organisms is a topic of great interest to evolutionary developmental biologists. Although developmental biologists have had great success in identifying the developmental mechanisms and molecular processes that specify organ size and shape within species, only relatively recently have the molecular tools become available to study how variation in these mechanisms gives rise to the phenotypic differences that are observed among closely related species. In addition to these technological advances, researchers interested in understanding how molecular variation gives rise to phenotypic variation have used three primary strategies to identify the molecular differences underlying species-specific traits: the candidate gene approach, differential gene expression screens, and between-species genetic mapping experiments. In this review, we discuss how these approaches have been successful in identifying the genes and the cellular mechanisms by which they specify variation in one of the most recognizable examples of the evolution of organ size, the adaptive variation in beak morphology among Darwin's finches. We also discuss insect reproductive structures as a model with great potential to advance our understanding of the specification and evolution of organ size and shape differences among species. The results from these two examples, and those from other species, show that species-specific variation in organ size and shape typically evolves via changes in the timing, location, and amount of gene/protein expression that act on tissue growth processes.
Assuntos
Evolução Biológica , Tentilhões , Insetos , Tamanho do Órgão , Tamanho do Órgão/genética , Animais , Tentilhões/anatomia & histologia , Insetos/anatomia & histologiaRESUMO
BACKGROUND: Thin endometrium (TE) is a challenging clinical issue in the reproductive medicine characterized by inadequate endometrial thickness, poor response to estrogen and no effective treatments currently. At present, the precise pathogenesis of thin endometria remains to be elucidated. We aimed to explore the related molecular mechanism of TE by comparing the transcriptome profiles of late-proliferative phase endometria between TE and matched controls. METHODS: We performed a bulk RNA-Seq (RNA-sequencing) of endometrial tissues in the late-proliferative phase in 7 TE and 7 matched controls for the first time. Differential gene expression analysis, gene ontology enrichment analysis and protein-protein interactions (PPIs) network analysis were performed. Immunohistochemistry was used for molecular expression and localization in endometria. Human endometrial stromal cells (HESCs) were isolated and cultured for verifying the functions of hub gene. RESULTS: Integrative data mining of our RNA-seq data in endometria revealed that most genes related to cell division and cell cycle were significantly inhibited, while inflammation activation, immune response and reactive oxygen species associated genes were upregulated in TE. PBK was identified as a hub of PPIs network, and its expression level was decreased by 2.43-fold in endometria of TE patients, particularly reduced in the stromal cells, which was paralleled by the decreased expression of Ki67. In vitro experiments showed that the depletion of PBK reduced the proliferation of HESCs by 50% and increased the apoptosis of HESCs by 1 time, meanwhile PBK expression was inhibited by oxidative stress (reduced by 76.2%), hypoxia (reduced by 51.9%) and inflammatory factors (reduced by approximately 50%). These results suggested that the insufficient expression of PBK was involved in the poor endometrial thickness in TE. CONCLUSIONS: The endometrial transcriptome in late-proliferative phase showed suppressed cell proliferation in women with thin endometria and decreased expression of PBK in human endometrial stromal cells (HESCs), to which inflammation and reactive oxygen species contributed.
Assuntos
Proliferação de Células/genética , Endométrio/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo/genética , Endométrio/metabolismo , Feminino , Humanos , Tamanho do Órgão/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA-Seq , Análise de Sequência de RNA , Células Estromais/metabolismo , Células Estromais/patologia , TranscriptomaRESUMO
Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.
Assuntos
Rim/fisiopatologia , Rim Policístico Autossômico Recessivo/mortalidade , Rim Policístico Autossômico Recessivo/fisiopatologia , Adolescente , Biomarcadores , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Lactente , Cirrose Hepática/fisiopatologia , Estudos Longitudinais , Masculino , Tamanho do Órgão/genética , Tamanho do Órgão/fisiologia , Rim Policístico Autossômico Recessivo/metabolismo , Prognóstico , Receptores de Superfície Celular/genética , Insuficiência Renal Crônica/fisiopatologia , UltrassonografiaRESUMO
In chronic obesity, activated adipose tissue proinflammatory cascades are tightly linked to metabolic dysfunction. Yet, close temporal analyses of the responses to obesogenic environment such as high-fat feeding (HFF) in susceptible mouse strains question the causal relationship between inflammation and metabolic dysfunction, and/or raises the possibility that certain inflammatory cascades play adaptive/homeostatic, rather than pathogenic roles. Here, we hypothesized that CTRP6, a C1QTNF family member, may constitute an early responder to acute nutritional changes in adipose tissue, with potential physiological roles. Both 3-days high-fat feeding (3dHFF) and acute obesity reversal [2-wk switch to low-fat diet after 8-wk HFF (8wHFF)] already induced marked changes in whole body fuel utilization. Although adipose tissue expression of classical proinflammatory cytokines (Tnf-α, Ccl2, and Il1b) exhibited no, or only minor, change, C1qtnf6 uniquely increased, and decreased, in response to 3dHFF and acute obesity reversal, respectively. CTRP6 knockout (KO) mouse embryonic fibroblasts (MEFs) exhibited increased adipogenic gene expression (Pparg, Fabp4, and Adipoq) and markedly reduced inflammatory genes (Tnf-α, Ccl2, and Il6) compared with wild-type MEFs, and recombinant CTRP6 induced the opposite gene expression signature, as assessed by RNA sequencing. Consistently, 3dHFF of CTRP6-KO mice induced a greater whole body and adipose tissue weight gain compared with wild-type littermates. Collectively, we propose CTRP6 as a gene that rapidly responds to acute changes in caloric intake, acting in acute overnutrition to induce a "physiological inflammatory response" that limits adipose tissue expansion.NEW & NOTEWORTHY CTRP6 (C1qTNF6), a member of adiponectin gene family, regulates inflammation and metabolism in established obesity. Here, short-term high-fat feeding in mice is shown to increase adipose tissue expression of CTRP6 before changes in the expression of classical inflammatory genes occur. Conversely, CTRP6 expression in adipose tissue decreases early in the course of obesity reversal. Gain- and loss-of-function models suggest CTRP6 as a positive regulator of inflammatory cascades, and a negative regulator of adipogenesis and adipose tissue expansion.
Assuntos
Adipocinas/fisiologia , Tecido Adiposo/patologia , Inflamação/genética , Fenômenos Fisiológicos da Nutrição/genética , Adipogenia/genética , Adipocinas/genética , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Dieta Hiperlipídica , Embrião de Mamíferos , Feminino , Células HEK293 , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tamanho do Órgão/genética , Hipernutrição/genética , Hipernutrição/metabolismo , Hipernutrição/patologia , GravidezRESUMO
Aquaculture production is expected to increase with the help of genomic selection (GS). The possibility of performing GS using only a small number of SNPs has been examined in order to reduce genotyping costs; however, the practicality of this approach is still unclear. Here, we tested whether the effects of reducing the number of SNPs impaired the prediction accuracy of GS for standard length, body weight, and testes weight in the tiger pufferfish (Takifugu rubripes). High values for predictive ability (0.563-0.606) were obtained with 4000 SNPs for all traits under a genomic best linear unbiased predictor (GBLUP) model. These values were still within an acceptable range with 1200 SNPs (0.554-0.588). However, predictive abilities and prediction accuracies deteriorated using less than 1200 SNPs largely due to the reduced power in accurately estimating the genetic relationship among individuals; family structure could still be resolved with as few as 400 SNPs. This suggests that the SNPs informative for estimation of genetic relatedness among individuals differ from those for inference of family structure, and that non-random SNP selection based on the effects on family structure (e.g., site-FST, principal components, or random forest) is unlikely to increase the prediction accuracy for these traits.
Assuntos
Genoma , Polimorfismo de Nucleotídeo Único , Takifugu/anatomia & histologia , Takifugu/genética , Testículo/anatomia & histologia , Animais , Masculino , Tamanho do Órgão/genéticaRESUMO
BACKGROUND: We compared skull shape and variation among genetically modified mice that exhibit different levels of connexin43 (Cx43) channel function, to determine whether Cx43 contributes to craniofacial phenotypic robustness. Specifically, we used two heterozygous mutant mouse models (G60S/+ and I130T/+) that, when compared to their wildtype counterparts, have an ~80% and ~50% reduction in Cx43 function, respectively. RESULTS: Both mutant strains showed significant differences in skull shape compared to wildtype littermates and while these differences were more severe in the G60S/+ mouse, shape differences were localized to similar regions of the skull in both mutants. However, increased skull shape variation was observed in G60S/+ mutants only. Additionally, covariation of skull structures was disrupted in the G60S/+ mutants only, indicating that while a 50% reduction in Cx43 function is sufficient to cause a shift in mean skull shape, the threshold for Cx43 function for disrupting craniofacial phenotypic robustness is lower. CONCLUSIONS: Collectively, our results indicate Cx43 can contribute to phenotypic robustness of the skull through a nonlinear relationship between Cx43 gap junctional function and phenotypic outcomes.
Assuntos
Conexina 43/fisiologia , Dureza/fisiologia , Crânio/fisiologia , Animais , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Tamanho do Órgão/genética , Fenótipo , Gravidez , Crânio/anatomia & histologia , Crânio/diagnóstico por imagemRESUMO
Sarcopenia, or age-related loss of muscle mass and strength, is an important contributor to loss of physical function in older adults. The pathogenesis of sarcopenia is likely multifactorial, but recently the role of neurological degeneration, such as motor unit loss, has received increased attention. Here, we investigated the longitudinal effects of muscle hypertrophy (via overexpression of human follistatin, a myostatin antagonist) on neuromuscular integrity in C57BL/6J mice between the ages of 24 and 27 months. Following follistatin overexpression (delivered via self-complementary adeno-associated virus subtype 9 injection), muscle weight and torque production were significantly improved. Follistatin treatment resulted in improvements of neuromuscular junction innervation and transmission but had no impact on age-related losses of motor units. These studies demonstrate that follistatin overexpression-induced muscle hypertrophy not only increased muscle weight and torque production but also countered age-related degeneration at the neuromuscular junction in mice.
Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Folistatina/farmacologia , Músculo Esquelético/patologia , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiologia , Animais , Feminino , Folistatina/genética , Folistatina/metabolismo , Expressão Gênica , Hipertrofia/genética , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genética , Sarcopenia/genética , Sarcopenia/prevenção & controle , Transmissão Sináptica/efeitos dos fármacosRESUMO
In the endocrine pancreas, growth hormone (GH) is known to promote pancreatic islet growth and insulin secretion. In this study, we show that GH receptor (GHR) loss in the germline and in adulthood impacts islet mass in general but more profoundly in male mice. GHR knockout (GHRKO) mice have enhanced insulin sensitivity and low circulating insulin. We show that the total cross-sectional area of isolated islets (estimated islet mass) was reduced by 72% in male but by only 29% in female GHRKO mice compared with wild-type controls. Also, islets from GHRKO mice secreted â¼50% less glucose-stimulated insulin compared with size-matched islets from wild-type mice. We next used mice with a floxed Ghr gene to knock down the GHR in adult mice at 6 mo of age (6mGHRKO) and examined the impact on glucose and islet metabolism. By 12 mo of age, female 6mGHRKO mice had increased body fat and reduced islet mass but had no change in glucose tolerance or insulin sensitivity. However, male 6mGHRKO mice had nearly twice as much body fat, substantially reduced islet mass, and enhanced insulin sensitivity, but no change in glucose tolerance. Despite large losses in islet mass, glucose-stimulated insulin secretion from isolated islets was not significantly different between male 6mGHRKO and controls, whereas isolated islets from female 6mGHRKO mice showed increased glucose-stimulated insulin release. Our findings demonstrate the importance of GH to islet mass throughout life and that unique sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose metabolism.NEW & NOTEWORTHY Growth hormone (GH) is important for more than just growth. GH helps to maintain pancreatic islet mass and insulin secretion throughout life. Sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose regulation despite losing islet mass.
Assuntos
Células Germinativas/metabolismo , Hormônio do Crescimento/deficiência , Ilhotas Pancreáticas/crescimento & desenvolvimento , Ilhotas Pancreáticas/fisiologia , Receptores da Somatotropina/genética , Fatores Etários , Animais , Proliferação de Células/genética , Feminino , Células Germinativas/fisiologia , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tamanho do Órgão/genética , Receptores da Somatotropina/deficiência , Receptores da Somatotropina/metabolismo , Caracteres Sexuais , Transdução de Sinais/genéticaRESUMO
It is well known that osteoporosis is a significant chronic disease with the increase of the aging population. Here, we report that expression of G protein-coupled receptor 35 (GPR35) in bone marrow mesenchymal stem cells (BMSCs) is suppressed in diagnosed osteoporosis patients and osteoporotic mice. The expression of GPR35 on BMSCs is enhanced during osteogenic differentiation. GPR35 knockout suppresses the proliferation and osteogenesis of BMSCs and deteriorates bone mass in both sham-treated and ovariectomized mice. Moreover, GPR35 deficiency reduces ß-catenin activity in BMSCs. In contrast, the overexpression of GPR35 contributes to these processes in BMSCs. Finally, using zaprinast, a synthetic GPR35 agonist, we show that zaprinast rescues OVX-induced bone loss and promotes bone generation in mice. Thus, GPR35 may as a new target and its agonist zaprinast may serve as a novel treatment for osteoporosis.
Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Osteogênese , Receptores Acoplados a Proteínas G/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Proliferação de Células , Feminino , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genética , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/prevenção & controle , Ovariectomia , Purinonas/farmacologia , Purinonas/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genéticaRESUMO
Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.
Assuntos
Densidade Óssea/genética , Osso e Ossos/metabolismo , Cromossomos de Mamíferos , Variação Genética , Osteoblastos/metabolismo , Proteínas Serina-Treonina Quinases , Transdução de Sinais/genética , Animais , Osso e Ossos/citologia , Cromossomos de Mamíferos/genética , Cromossomos de Mamíferos/metabolismo , Camundongos , Camundongos Knockout , Tamanho do Órgão/genética , Osteoblastos/citologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
miR156/157 plays multiple pivotal roles during plant growth and development. In this study, we identified 11 miR156- and 5 miR157-encoding loci from the genome of Petunia axillaris and Petunia inflata, designated as PaMIR0156/157s and PiMIR0156/157s, respectively. Real-time quantitative reverse transcription PCR (qRT-PCR) analysis indicated that PhmiR156/157 was expressed predominantly in cotyledons, germinating seeds, flower buds, young fruits and seedlings. PhmiR156/157 levels declined in shoot apical buds and leaves of petunia before flowering as the plant ages; moreover, the temporal expression patterns of most miR156/157-targeted PhSPLs were complementary to that of PhmiR156/157. Ectopic expression of PhMIR0157a in Arabidopsis and petunia resulted in delayed flowering, dwarf plant stature, increased branches and reduced organ size. However, PhMIR0156f-overexpressing Arabidopsis and petunia plants showed only delayed flowering. In addition, downregulation of PhmiR156/157 level by overexpressing STTM156/157 led to taller plants with less branches, longer internodes and precocious flowering. qRT-PCR analysis indicated that PhmiR156/157 modulates these traits mainly by downregulating their PhSPL targets and subsequently decreasing the expression of flowering regulatory genes. Our results demonstrate that the PhmiR156/157-PhSPL module has conserved but also divergent functions in growth and development, which will help us decipher the genetic basis for the improvement of flower transition, plant architecture and organ development in petunia.