Genetic and epigenetic control of retinal development in zebrafish

Abstract

The vertebrate retina is a complex structure composed of seven cell types (six neuron and one glia), and all of which originate from a seemingly homogeneous population of proliferative multipotent retinal progenitor cells (RPCs) that exit the cell cycle and differentiate in a spatio-temporally regulated and stereotyped fashion. This neurogenesis process requires intricate genetic regulation involving a combination of cell intrinsic transcription factors and extrinsic signaling molecules, and many critical factors have been identified that influence the timing and composition of the developing retina. Adding complexity to the process, over the past decade, a variety of epigenetic regulatory mechanisms have been shown to influence neurogenesis, and these include changes in histone modifications and the chromatin landscape and changes in DNA methylation and hydroxymethylation patterns. This review summarizes recent findings in the genetic and epigenetic regulation of retinal development, with an emphasis on the zebrafish model system, and it outlines future areas of investigation that will continue to push the field forward into the epigenomics era.

Figure 1

Schematic representation of retinal neurogenesis. Retinal progenitor cells (RPCs) give rise to all seven types of retinal cells (six neuron types and one glia cell type) over time, and this requires a precise orchestration of gene expression and epigenetic modifications.

Figure 2

(A) DNA constructs required for generating transgenic animals for scGESTALT experiment. One construct carries a heat inducible mCherry-tagged barcode array that can be edited, while another carries a heat inducible Cas9 and a coding sequence of sgRNAs targeting the barcode (modified from Raj et al., 2018). (B) Using scGESTALT, the methylome and transcriptome of each retinal cell can be profiled at specific time points, while also generating lineage tracing data based on the edited barcode, which will reveal the topology of the lineage tree and enable identification of intermediate cell types/differentiation states.