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, 10, 11, 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.

长期以来，神经元身份一直被认为是不可变的，因此一旦细胞获得特定的命运，它就会终生维持。¹研究使用有效转录因子的过表达对小鼠新皮质^{2 、3}和视网膜^{4 、5}中的神经元命运进行实验性重编程，通过揭示有丝分裂后神经元可以转换其身份来挑战这一概念。命运重编程是否是中枢神经系统 (CNS) 正常发育的一部分尚不清楚。虽然有一些关于无脊椎动物 6、7 和脊椎动物周围神经系统 8 生理细胞^命运重编程^的报道脊椎动物中枢神经系统中的内源性命运重编程尚未被记录。在这里，我们在斑马鱼视网膜的中间神经元谱系中展示了自发的命运重新规范。我们展示了视觉系统同源框 1 ( vsx1 ) 表达谱系，它仅与兴奋性双极细胞 (BC) 中间神经元相关联，9, 10, 11, 12 也产生抑制性无长突细胞 (ACs)。我们确定了 Notch 信号在赋予新生vsx1 BCs 可塑性中的作用，允许合适的转录因子程序将它们重新指定为 AC 命运。过度刺激 Notch 信号增强了这种生理表型，因此vsx1祖细胞的两个女儿都分化为 ACs 并部分分化vsx1 BC 可以转换为 AC。此外，可以模仿这种生理重新规范，以允许实验诱导完全不同的命运，即来自vsx1谱系的视网膜投射神经元的命运。我们的观察揭示了视网膜发育过程中细胞命运的意外可塑性。