Subtype-specific survival and regeneration of retinal ganglion cells in response to injury

Abstract

Retinal ganglion cells (RGCs) are a heterogeneous population of neurons that function synchronously to convey visual information through the optic nerve to retinorecipient target areas in the brain. Injury or disease to the optic nerve results in RGC degeneration and loss of visual function, as few RGCs survive, and even fewer can be provoked to regenerate their axons. Despite causative insults being broadly shared, regeneration studies demonstrate that RGC types exhibit differential resilience to injury and undergo selective survival and regeneration of their axons. While most early studies have identified these RGC types based their morphological and physiological characteristics, recent advances in transgenic and gene sequencing technologies have further enabled type identification based on unique molecular features. In this review, we provide an overview of the well characterized RGC types and identify those shown to preferentially survive and regenerate in various regeneration models. Furthermore, we discuss cellular characteristics of both the resilient and susceptible RGC types including the combinatorial expression of different molecular markers that identify these specific populations. Lastly, we discuss potential molecular mechanisms and genes found to be selectively expressed by specific types that may contribute to their reparative capacity. Together, we describe the studies that lay the important groundwork for identifying factors that promote neural regeneration and help advance the development of targeted therapy for the treatment of RGC degeneration as well as neurodegenerative diseases in general.

NFATc4 knockout promotes neuroprotection and retinal ganglion cell regeneration after optic nerve injury

“…However, which NFATc4-dependent changes in gene expression re ect a pro-survival response, improving RGC survival and delaying axonal degeneration, needs further attention. It has been recently demonstrated that among 46 different RGC subtypes distinguished by high-throughput single-cell RNA-seq [113],some types exhibit selective resilience to injury while others are more susceptible to degeneration and die quickly [114]. Since NFATc4 may affect the expression pro le of genes involved in apoptosis, certain types of RGCs may be more vulnerable because of their NFATc4 expression, consistent with our data that NFATc4 up-regulation peaked 1 day after ONC.…”

Inhibition of high-voltage-activated calcium currents by acute hypoxia in cultured retinal ganglion cells

“…There are various types of RGCs with specific gene expression, retinorecipient targets, morphological and physiological characteristics, and functions (Baden et al, 2021;Kim et al, 2021). Previous studies showed selective vulnerability of RGCs (Luo et al, 2009;Ou et al, 2016;Mayer et al, 2018) and typespecific survival and regeneration in response to different injuries (Tran et al, 2019;Tapia et al, 2022). Identification and classification of the general cellular mechanisms that either contribute to or inhibit type-specific RGC survival and regeneration are critical for the development of effective neuroprotective strategies.…”

Optic Nerve Regeneration in Diabetic Retinopathy: Potentials and Challenges Ahead

“…Potential preference for survival and axon regeneration of certain RGC subtypes has already been reported in human glaucoma patients [ 103 ] and mouse optic nerve crush models [ 104 ]. In the recent five years, the emergence of single-cell transcriptome sequencing led to a better understanding of RGC subtype specificity [ 100 , 105 , 106 ].…”