Some neural stem cells (NSCs) can delaminate and differentiate into neurons without undergoing cell division, in a process known as direct conversion. Here, Laure Bally-Cuif and colleagues carry out live imaging and genetic tracing of NSCs in the adult zebrafish pallium to search for factors that might underly these direct conversion events. They focus on caspases, since these proteases are known to have non-apoptotic roles during development, including the modulation of cell fate decisions. The authors generate a heritable lineage tracer that labels the progeny of cells in which non-apoptotic cleavage events have occurred. They use this new tool to demonstrate that non-apoptotic caspase activation in adult zebrafish NSCs correlates with a fate biased towards neuronal differentiation and lineage termination, and they go on to show that inducing non-apoptotic caspase activity can promote the direct conversion of NSCs. Analysis of single-cell RNA-sequencing data reveals that atf3, which encodes a transcription factor induced by non-apoptotic caspase activation, is expressed at any given time in a subset of pallial NSCs. Inhibiting Atf3 function reduces the bias towards neuronal differentiation. Mechanical wounding of the pallium appears to induce atf3 expression alongside non-apoptotic caspase events; again, these events correlate with neuronal differentiation. Overall, this work reveals a role for non-apoptotic caspases in promoting the direct conversion of NSCs.
