Notch-mediated re-specification of neuronal identity during central nervous system development

Neuronal identity has long been thought of as immutable, so that once a cell acquires a specific fate, it is maintained for life.(1) Studies using the overexpression of potent transcription factors to experimentally reprogram neuronal fate in the mouse neocortex(2,3) and retina(4,5) have challenged this notion by revealing that post-mitotic neurons can switch their identity. Whether fate reprogramming is part of normal development in the central nervous system (CNS) is unclear. While there are some reports of physiological cell fate reprogramming in invertebrates,(6,7) and in the vertebrate peripheral nervous system,(8) endogenous fate reprogramming in the vertebrate CNS has not been documented. Here, we demonstrate spontaneous fate re-specification in an interneuron lineage in the zebrafish retina. We show that the visual system homeobox 1 (vsx1)-expressing lineage, which has been associated exclusively with excitatory bipolar cell (BC) interneurons,(9-12) also generates inhibitory amacrine cells (ACs). We identify a role for Notch signaling in conferring plasticity to nascent vsx1 BCs, allowing suitable transcription factor programs to re-specify them to an AC fate. Overstimulating Notch signaling enhances this physiological phenotype so that both daughters of a vsx1 progenitor differentiate into ACs and partially differentiated vsx1 BCs can be converted into ACs. Furthermore, this physiological re-specification can be mimicked to allow experimental induction of an entirely distinct fate, that of retinal projection neurons, from the vsx1 lineage. Our observations reveal unanticipated plasticity of cell fate during retinal development.

Automated summary

Studies have shown spontaneous neuronal fate re-specification in the zebrafish retina, challenging the traditional view of neuronal identity as immutable. This unexpected plasticity in cell fate during retinal development suggests that post-mitotic neurons can switch their identity, highlighting a new aspect of neural development.