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1.
Nature ; 585(7825): 420-425, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879486

RESUMO

The opsin family of G-protein-coupled receptors are used as light detectors in animals. Opsin 5 (also known as neuropsin or OPN5) is a highly conserved opsin that is sensitive to visible violet light1,2. In mice, OPN5 is a known photoreceptor in the retina3 and skin4 but is also expressed in the hypothalamic preoptic area (POA)5. Here we describe a light-sensing pathway in which POA neurons that express Opn5 regulate thermogenesis in brown adipose tissue (BAT). We show that Opn5 is expressed in glutamatergic warm-sensing POA neurons that receive synaptic input from several thermoregulatory nuclei. We further show that Opn5 POA neurons project to BAT and decrease its activity under chemogenetic stimulation. Opn5-null mice show overactive BAT, increased body temperature, and exaggerated thermogenesis when cold-challenged. Moreover, violet photostimulation during cold exposure acutely suppresses BAT temperature in wild-type mice but not in Opn5-null mice. Direct measurements of intracellular cAMP ex vivo show that Opn5 POA neurons increase cAMP when stimulated with violet light. This analysis thus identifies a violet light-sensitive deep brain photoreceptor that normally suppresses BAT thermogenesis.


Assuntos
Cor , Luz , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Neurônios/efeitos da radiação , Opsinas/metabolismo , Área Pré-Óptica/citologia , Termogênese/efeitos da radiação , Tecido Adiposo Marrom/inervação , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos da radiação , Animais , Temperatura Corporal , Temperatura Baixa , AMP Cíclico/metabolismo , Feminino , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Opsinas/deficiência , Opsinas/genética , Termogênese/genética
2.
Invest Ophthalmol Vis Sci ; 58(11): 4644-4653, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28903150

RESUMO

Purpose: The cone-rod homeobox (CRX) transcription factor is essential for photoreceptor gene expression, differentiation, and survival. Human CRX mutations can cause dominant retinopathies of varying onset and phenotype severity. In animal models, dominant frameshift Crx mutations introduce a premature termination codon (PTC), producing inactive truncated proteins that interfere with normal CRX function. Previously, a mutant mouse, TVRM65, was reported to carry a recessive late PTC mutation, Crx-L253X. More detailed phenotype analysis of the pathogenicity of Crx-L253X sheds new light on the variability of CRX-linked diseases. Methods: Homozygous (L253X/X); heterozygous (L253X/+); Crx-/- and control C57BL/6J (WT) mice were analyzed at various ages for changes in retinal function (ERG), morphology (histology) and photoreceptor gene expression (qRT-PCR). Results: At 1 month, L253X/X mice lack visual function, show greater reductions in retinal thickness, and distinct gene expression changes relative to Crx-/-, suggesting that the phenotype of L253X/X is more severe than Crx-/-. L253X/+ mice have reduced rod/cone function, but normal retinal morphology at all ages tested. qRT-PCR assays described a complex phenotype in which both developing and mature photoreceptors are unable to maintain proper gene expression. L253X mRNA/protein is overexpressed relative to normal Crx, suggesting a pathogenic mechanism similar to early PTC mutations. However, the overexpression is less pronounced, correlating with a relatively mild dominant phenotype. Conclusions: The L253X mouse provides a valuable model for CRX-associated retinopathy. The pathogenicity of CRX frameshift mutations depends on the position of the PTC, which in turn determines the degree of mutant mRNA/protein overproduction.


Assuntos
Códon sem Sentido/genética , Mutação da Fase de Leitura , Genes Dominantes , Proteínas de Homeodomínio/genética , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/genética , Transativadores/genética , Animais , Western Blotting , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Retina/fisiopatologia , Degeneração Retiniana/patologia
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