Predicting the Regenerative Potential of Retinal Ganglion Cells Based on Developmental Growth Trajectories

Abstract

Retinal ganglion cells in the mammalian central nervous system fail to regenerate following injury, with the capacity to survive and regrow varying by cell type. This variability may be linked to differences in developmental programs that overlap with the genetic pathways that mediate regeneration. To explore this correlation, we compared the structural changes in mouse retinal ganglion cells during development with those occurring after axonal injury. The dendritic trees of over 1,000 ganglion cells were reconstructed at different developmental stages, revealing that each cell type follows a distinct timeline. ON-sustained (sON) cells reach maturity by P14, whereas ON-transient (tON) cells achieve their maximum dendritic size by P10. Modeling of the dendritic changes indicate that while sON and tON follow similar growth programs the onset of growth was later in sON. After optic nerve crush, the remodeling of dendritic architecture differed between the two cell-types. sON cells exhibited rapid dendritic shrinkage, while tON cells shrank more gradually with changes in branching features. Following injury, sON cells reverted to an earlier developmental state than tON cells. In addition, after co-deletion of PTEN and SOC3, neurons appeared to regress further back in developmental time. Our results provide evidence that a ganglion cells resilience to injury and regenerative potential is predicted by its maturation timeline. Understanding these intrinsic differences could inform targeted neuroprotective interventions.