RESUMO
The melanocortin-4 receptor (MC4-R) is a G protein-coupled, seven-transmembrane receptor expressed in the brain. Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. This syndrome recapitulates several of the characteristic features of the agouti obesity syndrome, which results from ectopic expression of agouti protein, a pigmentation factor normally expressed in the skin. Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R.
Assuntos
Marcação de Genes/métodos , Obesidade/genética , Receptores de Peptídeos/fisiologia , Animais , Glicemia/análise , Química Encefálica , Modelos Animais de Doenças , Ingestão de Alimentos , Feminino , Expressão Gênica , Heterozigoto , Homozigoto , Insulina/sangue , Leptina , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Obesidade/sangue , Pró-Opiomelanocortina/genética , Proteínas/análise , RNA Mensageiro/análise , Receptor Tipo 4 de Melanocortina , Receptores de Peptídeos/genética , Transdução de Sinais , Aumento de Peso/genéticaRESUMO
The mutated gene responsible for the tubby obesity phenotype has been identified by positional cloning. A single base change within a splice donor site results in the incorrect retention of a single intron in the mature tub mRNA transcript. The consequence of this mutation is the substitution of the carboxy-terminal 44 amino acids with 24 intron-encoded amino acids. The normal transcript appears to be abundantly expressed in the hypothalamus, a region of the brain involved in body weight regulation. Variation in the relative abundance of alternative splice products is observed between inbred mouse strains and appears to correlate with an intron length polymorphism. This allele of tub is a candidate for a previously reported diet-induced obesity quantitative trait locus on mouse chromosome 7.
Assuntos
Obesidade/genética , Proteínas/química , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Processamento Alternativo/genética , Processamento Alternativo/fisiologia , Animais , Sequência de Bases , Química Encefálica/fisiologia , Mapeamento Cromossômico , Clonagem Molecular , Éxons/genética , Expressão Gênica/fisiologia , Variação Genética , Hibridização In Situ , Resistência à Insulina/genética , Camundongos , Camundongos Obesos , Dados de Sequência Molecular , Mutação/genética , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/metabolismo , Homologia de Sequência de AminoácidosRESUMO
The survival of developing motor neurons depends on factors secreted from skeletal muscles and from cells within the central nervous system. Although several members of the nerve growth factor protein family [neurotrophins (NTs)] are able to maintain developing rat motor neurons in vitro, only the brain-derived neurotrophic factor has been shown to have significant effects on the survival of motor neurons in vivo. In the present study, we demonstrate that NT-4/5 also prevents injury-induced death of facial motor neurons in neonatal rats. Furthermore, facial motor neurons express a functional receptor for NT-4/5, whereas mRNA-encoding NT-4/5 can be detected in their environment throughout embryonic and postnatal life. Thus, both NT-4/5 and brain-derived neurotrophic factor may be physiological survival factors for facial motor neurons and may serve as therapeutic agents for motor neuron disease.
Assuntos
Nervo Facial/citologia , Neurônios Motores/citologia , Fatores de Crescimento Neural/fisiologia , Receptores de Fatores de Crescimento/fisiologia , Animais , Animais Recém-Nascidos , Sequência de Bases , Sobrevivência Celular , Primers do DNA/química , Expressão Gênica , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptor do Fator Neutrófico CiliarRESUMO
Differentiation, survival, and function of the vertebrate neurons are controlled by multiple, target-derived neurotrophic factors. The best characterized mammalian neurotrophic factors are four structurally related 13 to 14 kDa basic proteins, collectively known as neurotrophins. Here we describe the identification of a gene cluster localized on human chromosome 19 that contains neurotrophin-5 (NT-5) and that may encode three additional acidic members of this protein family. The three novel partial open reading frames (ORFs), designated neurotrophin-6-alpha (NT6-alpha), NT6-beta and NT6-gamma, are 95% identical to each other and 75% identical to NT5. The putative mature N-terminal portion of NT6 ORFs does not contain a typical dibasic cleavage site and lacks two out of six cysteines that are conserved among the neutrophins. The unique structures of NT6-alpha, -beta, and -gamma suggest that if the NT6 open reading frames indeed code for functional proteins, these proteins may display novel functions and may act through a distinct class of receptors. In the human, both NTF5 and NTF6 gene loci were mapped to chromosome 19 by Southern analysis of somatic cell hybrid panels. In mouse, the NT5 gene (Ntf-5) was assigned to chromosome 7 and no sequences representing NT6 homologs were identified.
Assuntos
Cromossomos Humanos Par 19 , Fatores de Crescimento Neural/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Clonagem Molecular , Humanos , Células Híbridas , Dados de Sequência Molecular , Família Multigênica , RoedoresRESUMO
In vertebrates, the formation and maintenance of neuronal connections are subject to regulation by multiple target-derived, diffusible (neurotrophic) factors. Here we describe the identification and characterization of a novel neurotrophic factor designated neurotrophin-5 (NT-5). NT-5 is structurally related to nerve growth factor and is expressed in embryonic as well as adult tissues. Recombinant NT-5 promotes the survival of peripheral sensory and sympathetic neurons and induces differentiation of the pheochromocytoma cell line PC12. NT-5 activates two trk-related tyrosine kinase receptors and shares these receptors with other neurotrophins. Activation of multiple receptors may permit a single neurotrophin to control target innervation by distinct neuronal populations. Receptor sharing could enable neurotrophic factors emanating from distinct targets to cooperate in regulating neurons with multiple connections.