Non-apoptotic caspase events and Atf3 expression underlie direct neuronal differentiation of adult neural stem cells.

Neural stem cells (NSCs) generate neurons over a lifetime in adult vertebrate brains. In the adult zebrafish pallium, NSCs persist long term through balanced fate decisions. These decisions include direct neuronal conversions, i.e. delamination and neurogenesis without a division. To characterize this process, we reanalyze intravital imaging data of adult pallial NSCs, and observe shared delamination dynamics between NSCs and committed neuronal progenitors. Searching for mechanisms predicting direct NSC conversions, we build an NSC-specific genetic tracer of Caspase3/7 activation (Cas3*/Cas7*) in vivo. We show that non-apoptotic Cas3*/7* events occur in adult NSCs and are biased towards lineage termination under physiological conditions, with a predominant generation of single neurons. We further identify the transcription factor Atf3 as necessary for this bias. Finally, we show that the Cas3*/7* pathway is engaged by NSCs upon parenchymal lesion and correlates with NSCs more prone to lineage termination and neuron formation. These results provide evidence for non-apoptotic caspase events occurring in vertebrate adult NSCs and link these events with the NSC fate decision of direct conversion, which is important for long-term NSC population homeostasis.