Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

Abstract

Retinal development is under the coordinated control of overlapping networks of signaling pathways and transcription factors. The paper was conceived as a review of the data and ideas that have been formed to date on homeobox genes mutations that lead to the disruption of eye organogenesis and result in inherited eye/retinal diseases. Many of these diseases are part of the same clinical spectrum and have high genetic heterogeneity with already identified associated genes. We summarize the known key regulators of eye development, with a focus on the homeobox genes associated with monogenic eye diseases showing retinal manifestations. Recent advances in the field of genetics and high-throughput next-generation sequencing technologies, including single-cell transcriptome analysis have allowed for deepening of knowledge of the genetic basis of inherited retinal diseases (IRDs), as well as improve their diagnostics. We highlight some promising avenues of research involving molecular-genetic and cell-technology approaches that can be effective for IRDs therapy. The most promising neuroprotective strategies are aimed at mobilizing the endogenous cellular reserve of the retina.

Keywords: animal models; gene and cell therapy; homeobox genes; inherited retinal diseases; molecular genetic diagnostics; retina.

Figure 1

Expression of homeobox genes in the adult mouse retina. The retinal architecture is detailed in the review. The cell-specific expression of genes is detected by single-cell RNA sequencing (data from https://eyeintegration.nei.nih.gov). The only genes which are known to associate with eye/retinal malformations in humans are shown. On the left: Retinal layers; on the right: homeobox genes indicated in the same color as the cell types expressed them. Abbreviations in parentheses show corresponding cell types. RPE, retinal pigment epithelium; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; C, cone; R, rod; HC, horizontal cell; AC, amacrine cell; cBC, cone bipolar cell; rBC, rod bipolar cell; MG, Muller glia; RGC, retinal ganglion cell; Mi, microglial cell. Modified from [13]. License to reproduce: https://creativecommons.org/licenses/by/4.0/.