RESUMO
Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2(tm1a/tm1a)) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2(tm1a/tm1a) mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2(tm1a/tm1a) mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Colesterol/sangue , Metabolismo Energético/genética , Proteínas Modificadoras da Atividade de Receptores/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Ansiedade/genética , Ansiedade/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Comportamento Animal/fisiologia , Peso Corporal/genética , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Ingestão de Alimentos/genética , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Knockout , Atividade Motora/genética , Neurônios/metabolismo , Ocitocina/genética , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteínas Modificadoras da Atividade de Receptores/genética , Proteínas Repressoras/genética , Hormônio Liberador de Tireotropina/genética , Hormônio Liberador de Tireotropina/metabolismoRESUMO
We have recently reported the preliminary characterisation of a novel EGF-related gene, Scube1 (signal peptide-CUB domain-EGF-related, gene 1), that is expressed prominently in the developing gonad, nervous system, somites, surface ectoderm and limb buds of the mouse. Here we describe the expression pattern of a closely related gene, Scube2 (also known as Cegp1), which maps to the distal region of mouse chromosome 7. Scube2 transcription is restricted to the embryonic neurectoderm but is also detectable in the adult heart, lung and testis.
Assuntos
Fator de Crescimento Epidérmico/biossíntese , Sistema Nervoso/embriologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Northern Blotting , Proteínas de Ligação ao Cálcio , Ectoderma/metabolismo , Hibridização In Situ , Peptídeos e Proteínas de Sinalização Intercelular , Pulmão/metabolismo , Masculino , Camundongos , Miocárdio/metabolismo , RNA Mensageiro/metabolismo , Testículo/metabolismo , Distribuição Tecidual , Transcrição GênicaRESUMO
The epidermal growth factor (EGF) superfamily comprises a diverse group of proteins that function as secreted signaling molecules, growth factors, and components of the extracellular matrix, many with a role in vertebrate development. We have isolated a novel mammalian gene encoding an EGF-related protein with a CUB (C1s-like) domain that defines a new mammalian gene family. The Scube1 (signal peptide-CUB domain-EGF-related 1) gene was isolated from a developing mouse urogenital ridge cDNA library and is expressed prominently in the developing gonad, nervous system, somites, surface ectoderm, and limb buds. We have mapped Scube1 to mouse chromosome 15 and show that it is orthologous to a human gene in the syntenic region of chromosome 22q13. We discuss the possible functions of this novel gene and its role in heritable disease in light of these data.
Assuntos
Fator de Crescimento Epidérmico/genética , Sequência de Aminoácidos , Animais , Astrocitoma/genética , Proteínas de Ligação ao Cálcio , Mapeamento Cromossômico , Cromossomos Humanos Par 22 , Clonagem Molecular , Embrião de Mamíferos , Fator de Crescimento Epidérmico/metabolismo , Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Dados de Sequência Molecular , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Distribuição TecidualRESUMO
The mammalian sex-determining pathway is controlled by the presence or absence of SRY expression in the embryonic gonad. Expression of SRY in males is believed to initiate a pathway of gene expression resulting in testis development. In the absence of SRY, ovary development ensues. Several genes have now been placed in this pathway but our understanding of it is far from complete and several functional classes of protein appear to be absent. Sex-determining genes frequently exhibit sexually dimorphic patterns of expression in the developing gonad both before and after overt differentiation of the testis or ovary. In order to identify additional sex-determining or gonadal differentiation genes we have examined gene expression in the developing gonads of the mouse using cDNA microarrays constructed from a normalized urogenital ridge library. We screened for genes exhibiting sexually dimorphic patterns of expression in the gonad at 12.5 and 13.5 days post-coitum, after overt gonad differentiation, by comparing complex cDNA probes derived from male and female gonadal tissue at these stages on micro-arrays. Using in situ hybridization analysis we show here that two genes identified by this screen, protease nexin-1 (Pn-1) and vanin-1 (Vnn1), exhibit male-specific expression prior to overt gonadal differentiation and are detected in the somatic portion of the developing gonad, suggesting a possible direct link to the testis-determining pathway for both genes.