RESUMEN
Ribosome biogenesis is an essential cellular process. Its impairment is associated with developmental defects and increased risk of cancer. The in vivo cellular responses to defective ribosome biogenesis and the underlying molecular mechanisms are still incompletely understood. In particular, the consequences of impaired ribosome biogenesis within the intestinal epithelium in mammals have not been investigated so far. Here we adopted a genetic approach to investigate the role of Notchless (NLE), an essential actor of ribosome biogenesis, in the adult mouse intestinal lineage. Nle deficiency led to defects in the synthesis of large ribosomal subunit in crypts cells and resulted in the rapid elimination of intestinal stem cells and progenitors through distinct types of cellular responses, including apoptosis, cell cycle arrest and biased differentiation toward the goblet cell lineage. Similar observations were made using the rRNA transcription inhibitor CX-5461 on intestinal organoids culture. Importantly, we found that p53 activation was responsible for most of the cellular responses observed, including differentiation toward the goblet cell lineage. Moreover, we identify the goblet cell-specific marker Muc2 as a direct transcriptional target of p53. Nle-deficient ISCs and progenitors disappearance persisted in the absence of p53, underlying the existence of p53-independent cellular responses following defective ribosome biogenesis. Our data indicate that NLE is a crucial factor for intestinal homeostasis and provide new insights into how perturbations of ribosome biogenesis impact on cell fate decisions within the intestinal epithelium.
Asunto(s)
Apoptosis/fisiología , Células Caliciformes/citología , Intestinos/citología , Biogénesis de Organelos , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/genética , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Hibridación in Situ , Ratones Noqueados , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Células Madre , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The transverse properties of an electron beam are characterized by two quantities, the emittance which indicates the electron beam extent in the phase space and the angular momentum which allows for nonplanar electron trajectories. Whereas the emittance of electron beams produced in a laser-plasma accelerator has been measured in several experiments, their angular momentum has been scarcely studied. It was demonstrated that electrons in a laser-plasma accelerator carry some angular momentum, but its origin was not established. Here we identify one source of angular-momentum growth and we present experimental results showing that the angular-momentum content evolves during the acceleration.
