RESUMO
Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem(-/-) background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.
Assuntos
Encéfalo/fisiologia , Degeneração Neural/etiologia , Proteínas Repressoras , Fatores de Transcrição/fisiologia , Animais , Apoptose , Corpo Estriado/patologia , Modulador de Elemento de Resposta do AMP Cíclico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Feminino , Humanos , Doença de Huntington/etiologia , Doença de Huntington/genética , Doença de Huntington/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/patologia , Peptídeos/genética , Fenótipo , Transdução de Sinais , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
Activating transcription factor 1 (ATF1), CREB, and the cyclic AMP (cAMP) response element modulatory protein (CREM), which constitute a subfamily of the basic leucine zipper transcription factors, activate gene expression by binding as homo- or heterodimers to the cAMP response element in regulatory regions of target genes. To investigate the function of ATF1 in vivo, we inactivated the corresponding gene by homologous recombination. In contrast to CREB-deficient mice, which suffer from perinatal lethality, mice lacking ATF1 do not exhibit any discernible phenotypic abnormalities. Since ATF1 and CREB but not CREM are strongly coexpressed during early mouse development, we generated mice deficient for both CREB and ATF1. ATF1(-/-) CREB(-/-) embryos die before implantation due to developmental arrest. ATF1(+/-) CREB(-/-) embryos display a phenotype of embryonic lethality around embryonic day 9.5 due to massive apoptosis. These results indicate that CREB and ATF1 act in concert to mediate signals essential for maintaining cell viability during early embryonic development.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Ligação a DNA , Fatores de Transcrição/metabolismo , Fator 1 Ativador da Transcrição , Animais , Apoptose/genética , Contagem de Células , Diferenciação Celular/genética , Sobrevivência Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perda do Embrião/genética , Perda do Embrião/patologia , Embrião de Mamíferos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Fenótipo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
The principal regulation of body growth is via a cascade of hormone signals emanating from the hypothalamus, by release of GHRH, which then directs the somatotroph cells of the pituitary to release GH into the blood stream. This in turn leads to activation of signal transducer and activator of transcription 5-dependent expression of genes such as IGF-I in hepatocytes, acid labile substance, and serine protease inhibitor 2.1, resulting in body growth. Here, using conditional cAMP response element binding protein (CREB) mutant mice, we show that loss of the CREB transcription factor in the brain, but not the pituitary, results in reduced postnatal growth consistent with dwarfism caused by GH deficiency. We demonstrate that although there appears to be no significant impact upon the expression of GHRH mRNA in CREB mutant mice, the amount of GHRH peptide is reduced. These findings show that CREB is required for the efficient production of GHRH in hypothalamus, in addition to its previously reported role in pituitary GH production and somatotroph expansion.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Nanismo/metabolismo , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Adeno-Hipófise/anormalidades , Adeno-Hipófise/metabolismo , Animais , Encéfalo/metabolismo , Cruzamentos Genéticos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Nanismo/genética , Feminino , Fertilidade/genética , Hormônio do Crescimento/metabolismo , Hipotálamo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Lactação/genética , Masculino , Camundongos , Camundongos Mutantes , Somatostatina/metabolismoRESUMO
Recent generation of genetically modified Creb1 mutant mice has revealed an important role for CREB (cAMP responsive element binding protein) and the related proteins CREM (cAMP responsive element modulator) and ATF1 (activating transcription factor 1) in cell survival, in agreement with previous studies using overexpression of dominant-negative CREB (dnCREB). CREB and ATF1 are abundantly expressed in T cells and are rapidly activated by phosphorylation when T cells are stimulated through the T cell antigen receptor. We show that T cell-specific loss of CREB in mice, in combination with the loss of ATF1, results in reduced thymic cellularity and delayed thymic recovery following sublethal irradiation but no changes in T cell development or activation. These data show that loss of CREB function has specific effects on thymic T lymphocyte proliferation and homeostasis in vivo.