RESUMO
CNVs, which are a type of structural variation, make a substantial impact on diverse characteristics in multiple species. Q-PCR and data association analysis were used for STAT5A gene copy in this study. This study aimed to investigate the copy number variation (CNV) of the STAT5A gene in seven Chinese cattle breeds, namely Qinchuan cattle, Xianan cattle, Yunling cattle, Ji'an cattle, Jiaxian Red cattle, Qaidam cattle, and Guyuan yellow cattle. Blood samples were collected for CNV typing, and the correlation between CNV type and growth traits was analyzed using SPSS 23.0 software and ANOVA. The findings revealed variations in the distribution of different copy number types among the different cattle breeds. Furthermore, association analysis demonstrated a positive impact of CNV in the STAT5A gene on cattle growth: in the JX, individuals with duplication types exhibited superior performance in terms of rump length (P < 0.05). Conversely, normal GY cattle demonstrated better body height and abdomen circumference (P < 0.05), while QD cattle exhibited a significant correlation between weight and body length with normal individuals (P < 0.05). Moreover, QC bovine duplication individuals outperformed other types, with copy number variation significantly associated with chest depth, chest width, and body length (P < 0.05). The results validate the correlation between copy number variation (CNV) of the STAT5A gene and growth characteristics in five different cattle breeds, providing a reliable benchmark for the purpose of cattle breeding.
Assuntos
Cruzamento , Variações do Número de Cópias de DNA , Fator de Transcrição STAT5 , Animais , Bovinos/genética , Peso Corporal/genética , Fenótipo , Fator de Transcrição STAT5/genética , Proteínas Supressoras de Tumor/genética , Crescimento/genéticaRESUMO
'Special issue - In Utero and Early Life Programming of Aging and Disease'. Skeletal muscle (SM) adaptations to physical exercise (PE) have been extensively studied due, not only to the relevance of its in situ plasticity, but also to the SM endocrine-like effects in noncontractile tissues, such as brain, liver or adipocytes. Regular PE has been considered a pleiotropic nonpharmacological strategy to prevent and counteract the deleterious consequences of several metabolic, cardiovascular, oncological and neurodegenerative disorders. Additionally, PE performed by parents seems to have a direct impact in the offspring through the transgenerational programming of different tissues, such as SM. In fact, SM offspring programming mechanisms seems to be orchestrated, at least in part, by epigenetic machinery conditioning transcriptional or post-transcriptional processes. Ultimately, PE performed in the early in life is also a critical window of opportunity to positively modulate the juvenile and adult phenotype. Parental PE has a positive impact in several health-related offspring outcomes, such as SM metabolism, differentiation, morphology and ultimately in offspring exercise volition and endurance. Also, early-life PE counteracts conceptional-related adverse effects and induces long-lasting healthy benefits throughout adulthood. Additionally, epigenetics mechanisms seem to play a key role in the PE-induced SM adaptations. Despite the undoubtedly positive role of parental and early-life PE on SM phenotype, a strong research effort is still needed to better understand the mechanisms that positively regulate PE-induced SM programming.
Assuntos
Exercício Físico/genética , Músculo Esquelético/crescimento & desenvolvimento , Epigênese Genética , Feminino , Crescimento/genética , Humanos , GravidezRESUMO
Gigantism results when one lineage within a clade evolves extremely large body size relative to its small-bodied ancestors, a common phenomenon in animals. Theory predicts that the evolution of giants should be constrained by two tradeoffs. First, because body size is negatively correlated with population size, purifying selection is expected to be less efficient in species of large body size, leading to increased mutational load. Second, gigantism is achieved through generating a higher number of cells along with higher rates of cell proliferation, thus increasing the likelihood of cancer. To explore the genetic basis of gigantism in rodents and uncover genomic signatures of gigantism-related tradeoffs, we assembled a draft genome of the capybara (Hydrochoerus hydrochaeris), the world's largest living rodent. We found that the genome-wide ratio of nonsynonymous to synonymous mutations (ω) is elevated in the capybara relative to other rodents, likely caused by a generation-time effect and consistent with a nearly neutral model of molecular evolution. A genome-wide scan for adaptive protein evolution in the capybara highlighted several genes controlling postnatal bone growth regulation and musculoskeletal development, which are relevant to anatomical and developmental modifications for an increase in overall body size. Capybara-specific gene-family expansions included a putative novel anticancer adaptation that involves T-cell-mediated tumor suppression, offering a potential resolution to the increased cancer risk in this lineage. Our comparative genomic results uncovered the signature of an intragenomic conflict where the evolution of gigantism in the capybara involved selection on genes and pathways that are directly linked to cancer.
Assuntos
Evolução Biológica , Tamanho Corporal/genética , Genoma , Roedores/genética , Animais , Feminino , Crescimento/genética , Família Multigênica , Neoplasias/genética , Roedores/crescimento & desenvolvimentoRESUMO
Los factores genéticos y ambientales interactúan durante todo el crecimiento. La talla final adulta, el ritmo o tempo de crecimiento y maduración, así como la maduración sexual, esquelética y dental, tienen una transmisibilidad entre 41 y 71%. El estirón puberal ocurre un año antes en africanos que en europeos y los asiáticos son intermedios. Esta heterogeneidad puberal dificulta el uso de una referencia internacional en esta etapa, aunque su valor al permitir la comparabilidad entre poblaciones es indiscutible, así como el hecho que no todos los países pueden desarrollar sus propias referencias. En la Región Latinoamericana, Argentina, Cuba y Venezuela desarrollaron referencias hace muchos años y recientemente, Colombia, Ecuador y Perú. En Venezuela, se realizó el Estudio Nacional de Crecimiento y Desarrollo Humano (ENCDH) y el Estudio Longitudinal de Caracas (ELAMC) para establecer patrones de referencia, relevantes debido a la maduración más temprana y a las diferencias significativas en crecimiento y maduración con los anglosajones. Así mismo se elaboró el Atlas de Maduración Ósea del Venezolano y se han construido Curvas para uso Clínico integrando ambos estudios. Debido a la disparidad en el uso de referencias- internacionales y nacionalesse está planificando un estudio multicéntrico, denominado PRONNA, de la línea de investigación sobre Crecimiento y Desarrollo en Niños y Adolescentes (CDNNA) del Grupo Transición Alimentaria y Nutricional (grupo TAN) para la escogencia definitiva de las referencias a ser usadas(au)
Genetic and environmental factors interact during growth. Final height, tempo of growth, sexual, skeletal and dental maturation have between 41 and 71% heritability. The puberal spurt occurs one year earlier in Africans than in European descendants, Asiatic are intermediate. This pubertal heterogeneity difficult the use of an international reference during this period, although its importance in the comparability of prevalences is unique, as well as the fact that many countries are unable to develop their own references. In the Latin American Region, Argentina, Cuba and Venezuela have long--standing references, Colombia, Ecuador and Perú only recently. In Venezuela, due to the earlier maturation and differences from puberty onwards with anglosaxons, the National Growth and Development Study and the Caracas Longitudinal Study were developed in order to obtain growth charts. Both studies integrated for Clinical Use dual use charts: an Atlas for Bone Maturity Asessment is also available. Due to the multiple use of references (national as well as international) a multicenter national study-PRONNA- is being planned in order to decide which reference is most adequate. This is part of the Growth and Development Research line of study of TAN Group (Food and Nutritional Transition Group)(AU)
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Fatores Socioeconômicos , Puberdade , Crescimento/genética , Pobreza , Maturidade Sexual , Classe Social , Crescimento e Desenvolvimento , Transição NutricionalRESUMO
Gonadal steroids modulate growth hormone (GH) secretion and the pubertal growth spurt via undefined central pathways. GH-releasing hormone (GHRH) neurons express estrogen receptor α (ERα) and androgen receptor (AR), suggesting changing levels of gonadal steroids during puberty directly modulate the somatotropic axis. We generated mice with deletion of ERα in GHRH cells (GHRHΔERα), which displayed reduced body length in both sexes. Timing of puberty onset was similar in both groups, but puberty completion was delayed in GHRHΔERα females. Lack of AR in GHRH cells (GHRHΔAR mice) induced no changes in body length, but puberty completion was also delayed in females. Using a mouse model with two reporter genes, we observed that, while GHRHtdTom neurons minimally colocalize with Kiss1hrGFP in prepubertal mice, â¼30% of GHRH neurons coexpressed both reporter genes in adult females, but not in males. Developmental analysis of Ghrh and Kiss1 expression suggested that a subpopulation of ERα neurons in the arcuate nucleus of female mice undergoes a shift in phenotype, from GHRH to Kiss1, during pubertal transition. Our findings demonstrate that direct actions of gonadal steroids in GHRH neurons modulate growth and puberty and indicate that GHRH/Kiss1 dual-phenotype neurons play a sex-specific role in the crosstalk between the somatotropic and gonadotropic axes during pubertal transition.SIGNIFICANCE STATEMENT Late maturing adolescents usually show delayed growth and bone age. At puberty, gonadal steroids have stimulatory effects on the activation of growth and reproductive axes, but the existence of gonadal steroid-sensitive neuronal crosstalk remains undefined. Moreover, the neural basis for the sex differences observed in the clinical arena is unknown. Lack of ERα in GHRH neurons disrupts growth in both sexes and causes pubertal delay in females. Deletion of androgen receptor in GHRH neurons only delayed female puberty. In adult females, not males, a subset of GHRH neurons shift phenotype to start producing Kiss1. Thus, direct estrogen action in GHRH/Kiss1 dual-phenotype neurons modulates growth and puberty and may orchestrate the sex differences in endocrine function observed during pubertal transition.
Assuntos
Receptor alfa de Estrogênio/fisiologia , Hormônio Liberador de Hormônio do Crescimento/fisiologia , Crescimento/fisiologia , Kisspeptinas/fisiologia , Maturidade Sexual/fisiologia , Transdução de Sinais/fisiologia , Animais , Receptor alfa de Estrogênio/genética , Feminino , Hormônios Esteroides Gonadais/sangue , Hormônios Esteroides Gonadais/fisiologia , Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/genética , Hipotálamo/metabolismo , Kisspeptinas/genética , Masculino , Camundongos , Camundongos Knockout , Receptores Androgênicos/fisiologia , Caracteres Sexuais , Maturidade Sexual/genética , Transdução de Sinais/genéticaRESUMO
Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222CâA, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598CâT) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).
Assuntos
Mutação em Linhagem Germinativa , Transtornos do Crescimento/genética , Hipoglicemia/genética , Fator 1 Induzível por Hipóxia/deficiência , Mitocôndrias/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Expressão Gênica , Crescimento/genética , Humanos , Masculino , Metaboloma/genética , Metaboloma/fisiologia , Síndrome , Adulto JovemRESUMO
The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in individuals with intellectual disability and brain overgrowth, with individual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.
Assuntos
Crescimento/genética , Mutação , Fatores de Transcrição NFI/genética , Anormalidades Múltiplas/genética , Animais , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Duplicação Gênica , Transtornos do Crescimento/genética , Humanos , Camundongos , Displasia Septo-Óptica/genética , SíndromeRESUMO
OBJECTIVE: Gangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis. DESIGN: We generated knockout (KO) mice by targeting the ß1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process. RESULTS: The GalNAcT and GD3S KO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. The GalNAcT KO mice showed significantly enhanced OA progression compared to GD3S mice in vivo. Both GalNAcT and GD3S KO mice showed severe IL-1α-induced cartilage degradation ex vivo. Phosphorylation of MAPKs was enhanced in both GalNAcT and GD3S KOs after IL-1α stimulation. Gangliosides modulated by GalNAcT or GD3S rescued an increase of MMP-13 induced by IL-1α in mice lacking GalNAcT or GD3S after exogenous replenishment in vitro. CONCLUSION: These data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated by GalNAcT are important for cartilage metabolism, suggesting that GalNAcT is a potential target molecule for the development of novel OA treatments.
Assuntos
Artrite Experimental/metabolismo , Cartilagem Articular/metabolismo , Gangliosídeos/fisiologia , Osteoartrite/metabolismo , Envelhecimento/fisiologia , Animais , Artrite Experimental/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Progressão da Doença , Gangliosídeos/deficiência , Gangliosídeos/farmacologia , Deleção de Genes , Crescimento/genética , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1alfa/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Metaloproteinase 13 da Matriz/biossíntese , Camundongos Knockout , N-Acetilgalactosaminiltransferases/deficiência , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/fisiologia , Óxido Nítrico/metabolismo , Osteoartrite/patologia , Sialiltransferases/deficiência , Sialiltransferases/genética , Sialiltransferases/fisiologia , Técnicas de Cultura de Tecidos , Regulação para Cima/fisiologia , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
Polymorphic adenoma gene 1 (PLAG1) is a member of the pleomorphic adenoma gene family. PLAG family of proteins as a nuclear transcription factor mainly play a role in regulating a variety of important genes in the body. The aim of this study was to examine the association of the PLAG1 polymorphism with growth traits in 566 cattle. A novel 19-bp indel mutation was identified in the PLAG1 by sequencing pooled DNA samples (Pool-Seq) and agarose gel electrophoresis methods. The PCR products of PLAG1 exhibited 3 genotypes and 2 alleles: 142â¯bp (denoted as W) and 123â¯bp (denoted as D). Genotype WW and allele W were predominant in the studied populations. In addition, the 19-bp indel was significantly associated with the growth traits in cattle breeds, with the hip width and rump length of Pinan cattle (Pâ¯<â¯0.05), heart girth and cannon bone circumference of Xianan cattle (Pâ¯<â¯0.01 or Pâ¯<â¯0.05), as well as the heart girth, hip width, hucklebone width, rump length, height at sacrum and chest depth of the Jiaxian cattle (Pâ¯<â¯0.05). Our results indicate that the Indel marker of PLAG1 gene can be used as candidate molecular markers for the breeding in cattle.
Assuntos
Bovinos/crescimento & desenvolvimento , Bovinos/genética , Proteínas de Ligação a DNA/genética , Mutação INDEL , Característica Quantitativa Herdável , Animais , Peso Corporal/genética , Cruzamento , Estudos de Associação Genética/veterinária , Marcadores Genéticos , Genótipo , Crescimento/genética , Fenótipo , Deleção de SequênciaRESUMO
CONTEXT: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. OBJECTIVE: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. PATIENTS AND METHODS: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. RESULTS: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. CONCLUSIONS: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
Assuntos
Agrecanas/genética , Nanismo/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria/métodos , Braquidactilia/genética , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Nanismo/tratamento farmacológico , Feminino , Crescimento/genética , Hormônio do Crescimento/uso terapêutico , Heterozigoto , Humanos , Lactente , Degeneração do Disco Intervertebral/genética , Deslocamento do Disco Intervertebral/genética , Masculino , Pessoa de Meia-Idade , Osteocondrite Dissecante/congênito , Osteocondrite Dissecante/genética , Linhagem , Fenótipo , Adulto JovemRESUMO
Objetivou-se com este estudo utilizar a técnica de análise de agrupamento para classificar modelos de regressão não lineares usados para descrever a curva de crescimento de frangos de corte, levando em consideração os resultados de diferentes avaliadores de qualidade de ajuste. Para tanto, utilizaram-se dados de peso corporal e idade dos seguintes grupos genéticos de frangos de corte: Cobb500, Hubbard Flex e Ross308, de ambos os sexos, constituindo, assim, seis classes. Foram ajustados 10 modelos não lineares, cuja qualidade de ajuste foi medida pelo coeficiente de determinação ajustado, pelos critérios de informação de Akaike e bayesiano, pelo quadrado médio do erro e pelo índice assintótico. A análise de agrupamento indicou os modelos logístico, Michaelis-Menten, Michaelis-Menten modificado e von Bertalanffy como os mais adequados à descrição das curvas de crescimento das seis classes estudadas.
The aim of this study was to classify non-linear models used to describe the growth curve of broilers using the cluster analysis technique, taking into account the results of different measures of quality adjustment regression. For this purpose, we used data of body weight and age the following genetic groups of broilers: Cobb500, Hubbard Flex and Ross308, of both sexes, thus constituting six classes. Ten non-linear models were fitted, the quality of fit was measured by the adjusted coefficient of determination, Akaike information criteria and Bayesian, mean square error and index asymptotic. Cluster analysis indicated the Logistico, Michaelis Menten, Michaelis Menten Modificado and von Bertalanffy models as the most appropriate description of the growth curves for the six classes studied.
Assuntos
Animais , Crescimento/genética , Galinhas/crescimento & desenvolvimento , Família Multigênica , Pesos e Medidas Corporais/veterinária , Tamanho Corporal , Genótipo , Dinâmica não LinearRESUMO
La displasia torácica asfixiante es una enfermedad infrecuente con compromiso multiorgánico y alta letalidad neonatal. Se presenta conbaja estatura, miembros cortos, tórax estrecho. Con la edad, hay mejoría respiratoria, pero aparición de compromiso renal, hepático, pancreático y/o retinal. Objetivo: Describir la evolución a largo plazo de 8 pacientes de un hospital de pediatría. Métodos: Se evaluaron retrospectivamente edad de diagnóstico, sexo, variables antropométricas, complicaciones y radiología. Resultados: Masculino/femenino, 6/2. Edad al momento del diagnóstico mediana: 2,54 años. Evolución: 8/8, compromiso respiratorio; 3/8, renal; 2/8, hepático; 1/8, oftalmológico; 1/8, cardíaco. Mediana de estatura al momento del diagnóstico: -1,76 DE; crecimiento posnatal y proporciones corporales, normales. Radiología: 8/8, tórax estrecho y braquifalangia en manos. 5/8, anomalías acetabulares. Discusión: Es recomendable un seguimiento para monitorear la función renal, hepática y ocular. El pediatra debería sospechar esta entidad ante un recién nacido con tórax estrecho y dificultad respiratoria.
Asphyxiating Thoracic Dysplasia is an uncommon condition with multiple organ afectation and high neonatal mortality. It presents with short stature, short extremities, narrow thorax. With growth, there is respiratory improvement, but emergence of renal, hepatic, pancreatic and/or retinal impairment. Objective: to describe the long-term evolution of 8 patients of a pediatric hospital. Methods: we retrospectively evaluated age at diagnosis, sex, anthropometric variables, complications and radiology. Results: male/female 6/2. Median age at diagnosis: 2.54 years. Evolution: 8/8 respiratory compromise, 3/8 kidney, liver 2/8, 1/8 ophthalmologic, cardiac 1/8. Median height at diagnosis -1.76 DS, normal postnatal growth and body proportions. Radiology: 8/8 narrow chest and brachyphalangia in hands. 5/8 acetabular abnormalities. Discussion: for surveillance it is recommended to monitor renal, liver and eye function. The pediatrician should suspect this entity in a newborn with narrow thorax and respiratory distress.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Tórax/patologia , Tórax/diagnóstico por imagem , Ciliopatias , Crescimento/genéticaRESUMO
Mammalian stanniocalcin-2 (STC2) is a secreted polypeptide widely expressed in developing and adult tissues. However, although transgenic expression in mice is known to cause severe dwarfism, and targeted deletion of STC2 causes increased postnatal growth, its precise biological role is still unknown. We found that STC2 potently inhibits the proteolytic activity of the growth-promoting metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). Proteolytic inhibition requires covalent binding of STC2 to PAPP-A and is mediated by a disulfide bond, which involves Cys-120 of STC2. Binding of STC2 prevents PAPP-A cleavage of insulin-like growth factor-binding protein (IGFBP)-4 and hence release within tissues of bioactive IGF, required for normal growth. Concordantly, we show that STC2 efficiently inhibits PAPP-A-mediated IGF receptor signaling in vitro and that transgenic mice expressing a mutated variant of STC2, STC2(C120A), which is unable to inhibit PAPP-A, grow like wild-type mice. Our work identifies STC2 as a novel proteinase inhibitor and a previously unrecognized extracellular component of the IGF system.
Assuntos
Glicoproteínas/metabolismo , Crescimento/genética , Proteína Plasmática A Associada à Gravidez/metabolismo , Proteólise , Sequência de Aminoácidos , Animais , Células Cultivadas , Cisteína/química , Cisteína/genética , Feminino , Glicoproteínas/química , Glicoproteínas/genética , Células HEK293 , Humanos , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Dados de Sequência Molecular , Mutação , Ligação Proteica , Receptor IGF Tipo 1/metabolismoRESUMO
Perlman syndrome is a rare autosomal recessively inherited congenital overgrowth syndrome characterized by polyhydramnios, macrosomia, characteristic facial dysmorphology, renal dysplasia and nephroblastomatosis and multiple congenital anomalies. Perlman syndrome is associated with high neonatal mortality and, survivors have developmental delay and a high risk of Wilms tumor. Recently a Perlman syndrome locus was mapped to chromosome 2q37 and homozygous or compound heterozygous mutations were characterized in DIS3L2. The DIS3L2 gene product has ribonuclease activity and homology to the DIS3 component of the RNA exosome. It has been postulated that the clinical features of Perlman syndrome result from disordered RNA metabolism and, though the precise targets of DIS3L2 have yet to be characterized, in cellular models DIS3L2 knockdown is associated with abnormalities of cell growth and division.
Assuntos
Exorribonucleases/genética , Macrossomia Fetal/genética , Predisposição Genética para Doença , Crescimento/genética , Tumor de Wilms/genética , HumanosRESUMO
NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression. Somatic dysregulation of NSD1 and EZH2 have been associated with tumorigenesis. NSD1, as a fusion transcript with NUP98, plays a key role in leukemogenesis, particularly childhood acute myeloid leukemia. EZH2 is a major proto-oncogene and mono- and biallelic activating and inactivating somatic mutations occur as early events in the development of tumors, particularly poor prognosis hematopoietic malignancies. Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains. EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined. Many additional questions about the molecular and clinical features of NSD1 and EZH2 remain unanswered. However, studies are underway to address these and, as more cases are ascertained and technology improves, it is hoped that these will, in time, be answered.
Assuntos
Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Complexo Repressor Polycomb 2/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Mutação em Linhagem Germinativa , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Proto-Oncogene Mas , Proto-OncogenesRESUMO
The Notch signalling pathway ligand delta-like 1 homologue (Dlk1, also named Pref1) is expressed throughout the developing pituitary and becomes restricted to mostly growth hormone (GH) cells within the adult gland. We have investigated the role of Dlk1 in pituitary development and function from late embryogenesis to adulthood using a mouse model completely lacking the expression of Dlk1. We confirm that Dlk1-null mice are shorter and weigh less than wild-type littermates from late gestation, at parturition and in adulthood. A loss of Dlk1 leads to significant reduction in GH content throughout life, whereas other pituitary hormones are reduced to varying degrees depending on sex and age. Both the size of the pituitary and the proportion of hormone-producing cell populations are unchanged, suggesting that there is a reduction in hormone content per cell. In vivo challenge of mutant and wild-type littermates with growth hormone-releasing hormone and growth hormone-releasing hexapeptide shows that reduced GH secretion is unlikely to account for the reduced growth of Dlk1 knockout animals. These data suggest that loss of Dlk1 gives rise to minor pituitary defects manifesting as an age- and sex-dependent reduction in pituitary hormone contents. However, Dlk1 expression in other tissue is most likely responsible for the weight and length differences observed in mutant animals.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Adeno-Hipófise/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Proteínas de Ligação ao Cálcio , Feminino , Crescimento/genética , Hormônio do Crescimento/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Entre el 8 y 10% de los niños atendidos en atención primaria, presentan una falta de progreso en el peso. El diagnóstico diferencial incluye ingesta calórica inadecuada, inadecuada absorción y metabolismo aumentado. Se reconoce a un niño que no sube de peso por su historia alimentaria, historia médica, historia social, historia familiar y evaluación del apetito. Entre las diferentes causas de falla para crecer están baja talla constitucional, abuso sexual, maltrato infantil, depresión postparto, enfermedad celíaca y esofagitis eosinofílica, entre otros. Entre los pilares en el manejo del niño que no progresa de peso están enfoque terapéutico, apoyo nutricional, hábitos dietéticos y manejo especializado.
Between 8 and 10% of children seen in primary care, have a lack of progress in weight. The differential diagnosis includes inadequate caloric intake, inadequate absorption and increased metabolism. It is recognized that a child does not gain weight by diet history, medical history, social history, family history and evaluation of appetite. Among the various causes of failure to thrive are constitutional short stature, sexual abuse, child abuse, postpartum depression, celiac disease and eosinophilic esophagitis, among others. Among the mainstays in the management of child weight are not progressing therapeutic approach, nutritional support, dietary habits and specialized management.
Assuntos
Humanos , Masculino , Feminino , Criança , Crescimento/fisiologia , Crescimento/genética , Desnutrição/classificação , Desnutrição/complicações , Desnutrição/congênito , Desnutrição/diagnóstico , Desnutrição/dietoterapia , Desnutrição/epidemiologia , Desnutrição/genética , Desnutrição/história , Desnutrição/mortalidade , Desnutrição/patologia , Desnutrição/prevenção & controleRESUMO
The International Stem Cell Initiative analyzed 125 human embryonic stem (ES) cell lines and 11 induced pluripotent stem (iPS) cell lines, from 38 laboratories worldwide, for genetic changes occurring during culture. Most lines were analyzed at an early and late passage. Single-nucleotide polymorphism (SNP) analysis revealed that they included representatives of most major ethnic groups. Most lines remained karyotypically normal, but there was a progressive tendency to acquire changes on prolonged culture, commonly affecting chromosomes 1, 12, 17 and 20. DNA methylation patterns changed haphazardly with no link to time in culture. Structural variants, determined from the SNP arrays, also appeared sporadically. No common variants related to culture were observed on chromosomes 1, 12 and 17, but a minimal amplicon in chromosome 20q11.21, including three genes expressed in human ES cells, ID1, BCL2L1 and HM13, occurred in >20% of the lines. Of these genes, BCL2L1 is a strong candidate for driving culture adaptation of ES cells.
Assuntos
Células-Tronco Embrionárias/citologia , Crescimento/genética , Células-Tronco Pluripotentes Induzidas/citologia , Proteínas de Ligação a RNA/metabolismo , Proteína bcl-X/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Cromossomos Humanos Par 20/genética , Evolução Clonal/genética , Metilação de DNA , Etnicidade/genética , Regulação da Expressão Gênica no Desenvolvimento , Variação Genética , Genótipo , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Proteína 1 Inibidora de Diferenciação/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/genética , Seleção Genética/genética , Proteína bcl-X/genéticaRESUMO
Foram utilizados 128.700, 44.227, 90.383, 47.506, 42.619, 45.057, 17.666 e 27.181 dados, respectivamente, de peso à desmama (PD), peso ao sobreano (PS), escore de umbigo à desmama (UD), escore de umbigo à desmama de macho (UDM), escore de umbigo à desmama de fêmea (UDF), escore de umbigo ao sobreano (US), escore de umbigo ao sobreano de macho (USM) e escore de umbigo ao sobreano de fêmea (USF) com o objetivo de estimar parâmetros genéticos de escore visual do umbigo e as respectivas correlações genéticas com as características de crescimento - peso à desmama e peso ao sobreano -, em bovinos da raça Nelore, aplicando-se um modelo animal em análises uni e bicaracterísticas. As estimativas de herdabilidade (h²) para as características UD, UDM, UDF, US, USM, USF, PD e PS foram de 0,14±0,01; 0,18±0,02; 0,15±0,01; 0,26±0,01; 0,32±0,03; 0,27±0,02, 0,29±0,01 e 0,27±0,02, respectivamente, em análises unicaracterísticas. Em análises bicaracterísticas, as estimativas de h² para UD, US, PD e PS foram de 0,15, 0,27, 0,29 e 0,45, respectivamente. As correlações genéticas estimadas entre UDM e UDF, entre USM e USF e entre UD e US foram positivas e altas, as correlações genéticas entre escore do umbigo e características de crescimento foram todas positivas e de magnitudes de baixa a moderada.
Records of 128,700, 44,227, 90,383; 47,506; 42,619; 45,057; 17,666 and 27,181 animals were analyzed, for weight at weaning (WW), yearling weight (YW), navel score at weaning (NW), male navel score at weaning (MNW), female navel score at weaning (FNW), navel score at yearling (NY), male navel score at yearling (MNY) and female navel score at yearling (FNY), respectively, to estimate genetic parameters of navel visual scores and growth traits in Nelore cattle, using uni and bi-traits analysis. Heritability estimates obtained by uni-traits analysis for NW, MNW, FNW, NY, MNY, FNY, WW and YW traits were 0.14±0.01; 0.18±0.02; 0.15±0,01; 0.26±0,01; 0.32±0.03; 0.27±0.02; 0.29±0.01 and 0.27±0.02, respectively. Heritability estimates obtained by bi-traits analysis of NW, NY, WW and YW were 0.15; 0.27; 0.29 and 0.45. Genetic correlations between MNW and FNW, between MNY and FNY and between NW and NY, were positive and high, suggesting that these traits were determined by the same genes. Genetic correlation between navel score and growth traits were all positive and of low to moderate magnitude.
Assuntos
Animais , Masculino , Feminino , Peso Corporal , Bovinos/crescimento & desenvolvimento , Prolapso , Prepúcio do Pênis/patologia , Moldes Genéticos , Umbigo/anatomia & histologia , Desmame , Crescimento/genética , Melhoramento GenéticoRESUMO
Prolactin (PRL) is known to play an essential role in mammary alveolar proliferation in the pregnant mouse, but its role in lactation has been more difficult to define. Genetic manipulations that alter expression of the PRL receptor and its downstream signaling molecules resulted in developmental defects that may directly or indirectly impact secretory activation and lactation. To examine the in vivo role of PRL specifically in lactation, bromocriptine (BrCr) was administered every 8 h to lactating mice on the second day postpartum, resulting in an ~95% decrease in serum PRL levels. Although morphological changes in secretory alveoli were slight, by 8 h of BrCr, pup growth was inhibited significantly. Phosphorylated STAT5 fell to undetectable levels within 4 h. Decreased milk protein gene expression, ß-casein, and α-lactalbumin, was observed after 8 h of treatment. To assess mammary-specific effects on lipid synthesis genes, we isolated mammary epithelial cells (MECs) depleted of mammary adipocytes. Expression of genes involved in glucose uptake, glycolysis, pentose phosphate shunt, de novo synthesis of fatty acids, and biosynthesis of triacylglycerides was decreased up to 19-fold in MECs by just 8 h of BrCr treatment. Glands from BrCr-treated mice showed a twofold reduction in intracellular cytoplasmic lipid droplets and a reduction in cytosolic ß-casein. These data demonstrate that PRL signaling regulates MEC-specific lipogenic gene expression and that PRL signals coordinate the milk synthesis and mammary epithelial cell survival during lactation in the mouse.