Correct cell number generation is central to tissue development. However, in vivo roles of coordinated proliferation of individual neural progenitors in regulating cell numbers of developing neural tissues and the underlying molecular mechanism remain mostly elusive. Here, we showed that wild-type (WT) donor retinal progenitor cells (RPCs) generated significantly expanded clones in host retinae with G1-lengthening by p15 (cdkn2a/b) overexpression (p15+) in zebrafish. Further analysis showed that cell adhesion molecule 3 (cadm3) was reduced in p15+ host retinae, and overexpression of either full-length or ectodomains of Cadm3 in p15+ host retinae markedly suppressed the clonal expansion of WT donor RPCs. Notably, WT donor RPCs in retinae with cadm3 disruption recapitulated expanded clones that were found in p15+ retinae. More strikingly, overexpression of Cadm3 without extracellular ig1 domain in RPCs resulted in expanded clones and increased retinal total cell number. Thus, homophilic interaction of Cadm3 provides an intercellular mechanism underlying coordinated cell proliferation to ensure cell number homeostasis of the developing neuroepithelia.
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 Notchdependent M€ uller glia (MG) generation in the developing zebrafish retina. In jab2b À/À 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 À/À mutants. Furthermore, we observe a severe and moderate decrease in the number of MGs in notch3 À/À and notch1b À/À mutants, respectively, and the activation of Notch3 or Notch1b rescues the MG loss in jag2b À/À 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.
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