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 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.