RESUMEN
The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.
Asunto(s)
Encéfalo/embriología , Encéfalo/metabolismo , Proteínas de Unión al ADN/genética , Genes Esenciales/genética , Discapacidad Intelectual/genética , Antígenos de Histocompatibilidad Menor/genética , Mutación/genética , Empalme del ARN/genética , Animales , Encéfalo/anomalías , Encéfalo/patología , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/metabolismo , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Discapacidades del Desarrollo/fisiopatología , Anomalías del Ojo/genética , Femenino , Haploinsuficiencia/genética , Cabeza/anomalías , Heterocigoto , Humanos , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Masculino , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Antígenos de Histocompatibilidad Menor/análisis , Antígenos de Histocompatibilidad Menor/metabolismo , Linaje , ARN Mensajero/análisis , Columna Vertebral/anomalías , Síndrome , Pez Cebra/anomalías , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
The gene SON is on human chromosome 21 (21q22.11) and is thought to be associated with hematopoietic disorders that accompany Down syndrome. Additionally, SON is an RNA splicing factor that plays a role in the transcription of leukemia-associated genes. Previously, we showed that mutations in SON cause malformations in human and zebrafish spines and brains during early embryonic development. To examine the role of SON in normal hematopoiesis, we reduced expression of the zebrafish homolog of SON in zebrafish at the single-cell developmental stage with specific morpholinos. In addition to the brain and spinal malformations we also observed abnormal blood cell levels upon son knockdown. We then investigated how blood production was altered when levels of son were reduced. Decreased levels of son resulted in lower amounts of red blood cells when visualized with lcr:GFP transgenic fish. There were also reduced thrombocytes seen with cd41:GFP fish, and myeloid cells when mpx:GFP fish were examined. We also observed a significant decrease in the quantity of T cells, visualized with lck:GFP fish. However, when we examined their hematopoietic stem and progenitor cells (HSPCs), we saw no difference in colony-forming capability. These studies indicate that son is essential for the proper differentiation of the innate and adaptive immune system, and further investigation determining the molecular pathways involved during blood development should elucidate important information about vertebrate HSPC generation, proliferation, and differentiation.
Asunto(s)
Embrión no Mamífero/citología , Hematopoyesis , Pez Cebra/embriología , Animales , Animales Modificados Genéticamente/embriología , Diferenciación Celular , Proliferación Celular , Proteínas de Unión al ADN/fisiología , Enfermedades Hematológicas/metabolismo , Células Madre Hematopoyéticas/citología , Humanos , Antígenos de Histocompatibilidad Menor/fisiología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/fisiologíaRESUMEN
The sexes show profound differences in responses to infection and the development of autoimmunity. Dimorphisms in immune responses are ubiquitous across taxa, from arthropods to vertebrates. Drosophila melanogaster shows strong sex dimorphisms in immune system responses at baseline, upon pathogenic challenge, and over aging. We have performed an exhaustive survey of peer-reviewed literature on Drosophila immunity, and present a database of publications indicating the sex(es) analyzed in each study. While we found a growing interest in the community in adult immunity and in reporting both sexes, the main body of work in this field uses only one sex, or does not stratify by sex. We synthesize evidence for sexually dimorphic responses to bacterial, viral, and fungal infections. Dimorphisms may be mediated by distinct immune compartments, and we review work on sex differences in behavioral, epithelial, cellular, and systemic (fat body-mediated) immunity. Emerging work on sexually dimorphic aging of immune tissues, immune senescence, and inflammation are examined. We consider evolutionary drivers for sex differences in immune investment, highlight the features of Drosophila biology that make it particularly amenable to studies of immune dimorphisms, and discuss areas for future exploration.