RESUMEN
First insights into the molecular programs orchestrating the progression from neural stem cells to cortical projection neurons are emerging. Loss of the transcriptional regulator Ski has been linked to the human 1p36 deletion syndrome, which includes central nervous system defects. Here, we report critical roles for Ski in the maintenance of the neural stem cell pool and the specification of callosal neurons. Ski-deficient callosal neurons lose their identity and ectopically express the transcription factor Ctip2. The misspecified callosal neurons largely fail to form the corpus callosum and instead redirect their axons toward subcortical targets. We identify the chromatin-remodeling factor Satb2 as a partner of Ski, and show that both proteins are required for transcriptional repression of Ctip2 in callosal neurons. We propose a model in which Satb2 recruits Ski to the Ctip2 locus, and Ski attracts histone deacetylases, thereby enabling the formation of a functional nucleosome remodeling and deacetylase repressor complex. Our findings establish a central role for Ski-Satb2 interactions in regulating transcriptional mechanisms of callosal neuron specification.
Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Cuerpo Calloso/citología , Proteínas de Unión al ADN/fisiología , Proteínas de Unión a la Región de Fijación a la Matriz/fisiología , Proteínas del Tejido Nervioso/fisiología , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Proteínas Represoras/biosíntesis , Factores de Transcripción/fisiología , Proteínas Supresoras de Tumor/biosíntesis , Agenesia del Cuerpo Calloso/embriología , Agenesia del Cuerpo Calloso/genética , Agenesia del Cuerpo Calloso/patología , Animales , Axones/ultraestructura , Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica , Histona Desacetilasas/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/deficiencia , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Ratones , Ratones Noqueados , Ratones Mutantes Neurológicos , Modelos Genéticos , Complejos Multiproteicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Neurogénesis/genética , Nucleosomas/metabolismo , Mapeo de Interacción de Proteínas , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Skin colonization by human papillomavirus (HPV) is typically related to inconspicuous cutaneous infections without major disease or complications in immunocompetent individuals. However, in immunosuppressed patients, especially organ transplanted recipients, cutaneous HPV infections may cause massive, highly spreading and recurrent skin lesions upon synergism with UV-exposure. Current HPV prophylactic vaccines are not effective against cutaneous HPV types (cHPV). By applying a modular polytope-based approach, in this work, we explored different vaccine candidates based on selected, tandemly arranged cHPV-L2 epitopes fused to thioredoxin (Trx) as a scaffold protein. Upon conversion to heptameric nanoparticles with the use of a genetically fused oligomerization domain, our candidate Trx-L2 vaccines induce broadly neutralizing immune responses against 19 cHPV in guinea pigs. Similar findings were obtained in mice, where protection against virus challenge was also achieved via passive transfer of immune sera. Remarkably, immunization with the candidate cHPV vaccines also induced immune responses against several mucosal low- and high-risk HPV types, including HPV16 and 18. Based on cumulative immunogenicity data but also on ease and yield of production, we identified a lead vaccine candidate bearing 12 different cHPV-L2 epitopes that holds great promise as a scalable and GMP production-compatible lead molecule for the prevention of post-transplantation skin lesions caused by cHPV infection.