RESUMEN
Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulin-growth factor 2 (Igf2) and downregulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17-19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.
Asunto(s)
Extinción Psicológica/fisiología , Miedo/fisiología , Regulación de la Expresión Génica , Hipocampo/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Memoria/fisiología , Animales , Animales Recién Nacidos , Proliferación Celular , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Neuronas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Transducción de Señal , Factores de TiempoRESUMEN
Increasing evidence suggests an important function of the ß-amyloid precursor protein (APP) in malignant disease in humans; however, the biological basis for this evidence is not well understood at present. To understand the role of APP in transformed pluripotent stem cells, we studied its expression levels in human testicular germ cell tumors using patient tissues, model cell lines, and an established xenograft mouse model. In the present study, we demonstrate the cooperative expression of APP with prominent pluripotency-related genes such as Sox2, NANOG, and POU5F1 (Oct3/4). The closest homologue family member, APLP2, showed no correlation to these stem cell factors. In addition, treatment with histone deacetylase (HDAC) inhibitors suppressed the levels of APP and stem cell markers. Loss of pluripotency, either spontaneously or as a consequence of treatment with an HDAC inhibitor, was accompanied by decreased APP protein levels both in vitro and in vivo. These observations suggest that APP represents a novel and specific biomarker in human transformed pluripotent stem cells that can be selectively modulated by HDAC inhibitors.
Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de Células Germinales y Embrionarias/metabolismo , Células Madre Pluripotentes/metabolismo , Neoplasias Testiculares/metabolismo , Adolescente , Adulto , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/farmacología , Animales , Biomarcadores de Tumor/genética , Diferenciación Celular/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Masculino , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/patología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Recombinantes/farmacología , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/patología , Transcripción Genética/efectos de los fármacos , Células Tumorales Cultivadas , Ácido Valproico/farmacología , Ácido Valproico/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain.