Timothy M. Gomez, PhD – Slide of the Week

Timothy M. Gomez, PhD - Slide of the Week

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

Legend: A graphical abstract representing the major findings of this paper.  Early-born, stem-cell-derived human photoreceptors (PRs) extend axons cell autonomously. Later-born PRs and all rod PRs extend axons via association with motile cells. Mature PR terminals are immobile, highly adherent with disorganized cytoskeletons. Mature PR have increased targeting of synaptic markers to their terminals. The two-photon microscope image on the right shows PRs developing within a retinal organoid, color-coded by depth.

Citation: Rempel, S.K., Welch, M.J., Ludwig, A.L., Phillips, J., Kancherla, Y., Zack, D.J., Gamm, D.M., and Gómez, T.M. (2022) Human photoreceptors switch from autonomous axon extension to cell-mediated process pulling during synaptic marker redistribution. Cell Reports. May 17;39(7). PMID: 35584680.

Abstract: 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. 

About the Lab: The Gomez laboratory focuses on the intracellular mechanisms that regulate growth cone motility and behavior. Growth cones are sensory-motor specializations at the tips of all growing axons and dendrites that detect and transduce extracellular cues into guided outgrowth. Great advances have been made in recent years in our understanding of the factors that contribute to guided axon extension. Many new classes of ligands and their receptors have been discovered and we are beginning to appreciate how growth cones integrate multiple extracellular stimuli and convert those signals into stereotyped behaviors.

Investigator: Timothy M. Gomez, PhD 

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