Nucleolar stress inDrosophilaneuroblasts, a model for human ribosomopathies

Abstract

ABSTRACTDifferent stem cells or progenitor cells display variable threshold requirements for functional ribosomes. For instance, select embryonic neural crest cells or adult bone marrow stem cells, but not others, show lethality due to failures in ribosome biogenesis or function (known as nucleolar stress) in several human ribosomopathies. To determine if variousDrosophilaneuroblasts display differential sensitivities to nucleolar stress, we used CRISPR-Cas9 to disrupt theNopp140gene that encodes two ribosome biogenesis factors (RBFs). Disruption ofNopp140induced nucleolar stress that arrested larvae in the second instar stage. While the majority of larval neuroblasts arrested development, the Mushroom Body (MB) neuroblasts continued to proliferate as shown by their maintenance of deadpan, a neuroblast-specific transcription factor, and by their continued EdU incorporation. MB neuroblasts in wild type larvae contained more fibrillarin and Nopp140 in their nucleoli as compared to other neuroblasts, indicating that MB neuroblasts stockpile RBFs as they proliferate in late embryogenesis while other neuroblasts normally enter quiescence. A greater abundance of Nopp140 encoded by maternal transcripts inNopp140−/−MB neuroblasts likely rendered these cells more resilient to nucleolar stress.Summary StatementNucleolar stress (loss of ribosome production/function) in certain human stem cells or progenitor cells results in disease. In fruit flies, larval Mushroom Body neuroblasts are relatively resilient to nucleolar stress.