Jag2b-Notch3/1b-mediated neuron-to-glia crosstalk controls retinal gliogenesis

In the developing central nervous systems (CNS), neural progenitor cells generate neurons and glia in a sequential order. However, the influence of neurons on glia generation remains elusive. Here we report that photoreceptor cell-derived Jag2b is required for Notch-dependent Müller glia (MG) generation in the developing zebrafish retina. In jab2b-/- mutants, differentiating MGs are re-specified into lineage-related bipolar neuron fate at the expense of mature MG. Single-cell transcriptome analysis and knock-in animals reveal that jab2b is specifically expressed in crx+-photoreceptor cells during MG generation. Crx promoter-driven jag2b, but not other Notch ligands, is sufficient to rescue the loss of MGs observed in jag2b-/- mutants. Furthermore, we observe a severe and moderate decrease in the number of MGs in notch3-/- and notch1b-/- mutants, respectively, and the activation of Notch3 or Notch1b rescues the MG loss in jag2b-/- mutants. Together, our findings reveal that the interaction of Jag2b and Notch3/Notch1b mediates the crosstalk between neurons and glial cells to ensure the irreversible differentiation of MG, providing novel mechanistic insights into the temporal specification of glial cell fate in a developing vertebrate CNS structure.