Human photoreceptors switch from autonomous axon extension to cell-mediated process pulling during synaptic marker redistribution.

Photoreceptors (PRs) are the primary visual sensory cells, and their loss leads to blindness that is currently incurable. Although cell replacement therapy holds promise, success is hindered by our limited understanding of PR axon growth during development and regeneration. Here, we generate retinal organoids from human pluripotent stem cells to study the mechanisms of PR process extension. We find that early-born PRs exhibit autonomous axon extension from dynamic terminals. However, as PRs age from 40 to 80 days of differentiation, they lose dynamic terminals on 2D substrata and in 3D retinal organoids. Interestingly, PRs without motile terminals are still capable of extending axons but only by process stretching via attachment to motile non-PR cells. Immobile PR terminals of late-born PRs have fewer and less organized actin filaments but more synaptic proteins compared with early-born PR terminals. These findings may help inform the development of PR transplantation therapies.