RESUMEN
The contribution of microglia in neurological disorders is emerging as a leading disease driver rather than a consequence of pathology. RNAseT2-deficient leukoencephalopathy is a severe childhood white matter disorder affecting patients in their first year of life and mimicking a cytomegalovirus brain infection. The early onset and resemblance of the symptoms to a viral infection suggest an inflammatory and embryonic origin of the pathology. There are no treatments available for this disease as our understanding of the cellular drivers of the pathology are still unknown. In this study, using a zebrafish mutant for the orthologous rnaset2 gene, we have identified an inflammatory signature in early development and an antiviral immune response in mature adult brains. Using the optical transparency and the ex utero development of the zebrafish larvae we studied immune cell behavior during brain development and identified abnormal microglia as an early marker of pathology. Live imaging and electron microscopy identified that mutant microglia displayed an engorged morphology and were filled with undigested apoptotic cells and undigested substrate. Using microglia-specific depletion and rescue experiments, we identified microglia as drivers of this embryonic phenotype and potential key cellular player in the pathology of RNAseT2-deficient leukoencephalopathy. Our zebrafish model also presented with reduced survival and locomotor defects, therefore recapitulating many aspects of the human disease. Our study therefore placed our rnaset2 mutant at the forefront of leukodystrophy preclinical models and highlighted tissue-specific approaches as future therapeutic avenues.
Asunto(s)
Apoptosis/fisiología , Encéfalo/metabolismo , Leucoencefalopatías/patología , Microglía/metabolismo , Animales , Leucoencefalopatías/metabolismo , Mutación/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Fenotipo , Pez Cebra , Proteínas de Pez Cebra/metabolismoRESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.
Asunto(s)
Linfocitos B , Transformación Celular Neoplásica , Linfoma de Células B Grandes Difuso , Proteínas de Neoplasias , Animales , Humanos , Ratones , Afinidad de Anticuerpos/genética , Linfocitos B/patología , Centro Germinal , Mutación , Proteínas de Neoplasias/genética , Linfoma de Células B Grandes Difuso/genética , Transformación Celular Neoplásica/genética , Selección GenéticaRESUMEN
Endogenous retroviruses (ERVs) are fossils left in our genome from retrovirus infections of the past. Their sequences are part of every vertebrate genome and their random integrations are thought to have contributed to evolution. Although ERVs are mainly silenced by the host genome, they have been found to be activated in multiple disease states, such as auto-inflammatory disorders and neurological diseases. However, the numerous copies in mammalian genomes and the lack of tools to study them make defining their role in health and diseases challenging. In this study, we identified eight copies of the zebrafish endogenous retrovirus zferv. We created and characterised the first in vivo ERV reporter line in any species. Using a combination of live imaging, flow cytometry and single-cell RNA sequencing, we mapped zferv expression to early T cells and neurons. Thus, this new tool identified tissues expressing ERV in zebrafish, highlighting a potential role of ERV during brain development and strengthening the hypothesis that ERV play a role in immunity and neurological diseases. This transgenic line is therefore a suitable tool to study the function of ERV in health and diseases.
Asunto(s)
Retrovirus Endógenos , Infecciones por Retroviridae , Animales , Animales Modificados Genéticamente , Retrovirus Endógenos/genética , Mamíferos , Neuronas , Infecciones por Retroviridae/genética , Pez Cebra/genéticaRESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.