A gene regulatory hierarchy for retinal ganglion cell specification and differentiation

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Abstract

Retinal ganglion cells (RGCs) are the first cell type to be specified during vertebrate retinogenesis. Specification and differentiation of the RGC lineage are a stepwise process involving a hierarchical gene regulatory network. During the past decade, a framework of the network has emerged and key transcriptional regulators have been identified. Pax6, Notch, Ath5, and the Brn3 (Pou4f) factors act at different levels of the regulatory hierarchy. In this review, we summarize the current understanding of the functions of these and other transcriptional factors in the specification and differentiation of the RGC lineage. We emphasize the regulatory relationships among transcription factors at different steps of RGC development. We discuss critical issues that need to be addressed before a complete understanding of the gene regulatory network for RGC development can be achieved. Future directions in RGC development will inevitably rely on combined genetic and genomics approaches.

Introduction

Cell specification and differentiation are fundamental processes of animal development and are subject to extensive and precise regulation at the molecular level. For any specific cell type, key regulatory players, including intrinsic transcription factors and extrinsic signaling molecules, are required [1], [2], [3]. Cell specification and differentiation in the vertebrate retina have been studied extensively and significant progress has been made, particularly with the advent of gene knockout mouse models with retinal defects. The development of the vertebrate retina and the molecular mechanisms involved are highly conserved among vertebrate species. During development, the six neuronal cell types (rod and cone photoreceptors, bipolar cells, horizontal cells, amacrine cells, and retinal ganglion cells (RGCs)) and one glial cell type (Muller cells) in the mature retina all arise from the same population of retinal neuroblasts [4], [5]. Specification of these cell types follows a distinct temporal and spatial order [6], [7], [8], [9], [10]. It has been proposed that the temporally ordered birth of the different cell types is due to intrinsic changes of retinal progenitor cells over time, resulting in corresponding changes in their competence to become different cell types [4], [7]. Although how this competence change occurs is not well understood, many genes involved in the specification and differentiation of different retinal cell types have been identified [4], [5], [11]. In this review, we focus on the current understanding of the molecular regulatory events that occur during the specification and differentiation of RGCs, the earliest retinal cell type to be specified. We also discuss the technical advances that will eventually lead to a comprehensive model of the gene regulatory network for RGC specification and differentiation. We distinguish specification from differentiation not necessarily to imply well-defined transitions in cell state but rather to indicate that the starting point of RGC formation, namely an undifferentiated cell dedicated to an RGC fate, differs from the later steps of overt morphological differentiation. The terms specification, determination, and commitment are used interchangeably to indicate that a progenitor cell has become dedicated to an RGC fate. We use the term competence to define a cell (or field of cells) that has the potential to become an RGC but may follow another fate, depending on its intrinsic and extrinsic environments.

Section snippets

Lineage history of RGCs

In the mouse, RGCs first appear at embryonic day (E) 11.5, when progenitor cells exit the cell cycle and begin to express early RGC markers. Specification of RGCs starts from the center of the retina and expands anteriorly toward the periphery [6], [12], [13]. How RGC specification is initiated from a seemingly uniform population of naı̈ve retinal neuroblasts is unclear. That RGC specification starts at the center of the retina indicates that inductive cues from neighboring structures, possibly

Hierarchical gene regulatory network for RGC specification

RGC formation is a continuation of the early morphological and molecular processes of retina development. RGC specification and differentiation proceed as a stepwise process when the retina has developed to a certain stage. A specific gene regulatory program is required to accomplish each step. Thus, gene regulation during RGC formation is inherently hierarchical, with transcription factors regulating the early events positioned at the top of the hierarchy and those for the late events at the

Transcriptional regulation during RGC differentiation

Once committed to its fate, an RGC precursor undergoes terminal differentiation to become a functionally mature RGC. Like all specialized neurons, RGCs differentiate in several stages [48]. First, committed cells migrate to the innermost layer of the retinal epithelium, the future ganglion cell layer. At the same time, the cells establish their apical–basal polarity and send out axons and dendrites. The dendritic projections make connections with the amacrine, bipolar, and horizontal

Not all RGCs are the same

Mature RGCs are not a homogeneous population. Distinct RGC subtypes can be identified based on their morphology, physiological functions and axon projection patterns. RGCs vary in soma size and morphology, and there are 10–15 different RGC types in different species [48], [69]. There is considerable variability in the composition of different-sized RGCs in the retinas of mammalian species [48]. For example, based on soma size, there are three major types of RGCs in primates; parasol (the

Perspectives

Although substantial progress has been made in determining the genetic and molecular bases of RGC specification and differentiation, obtaining a comprehensive picture of the gene regulatory network driving these processes continues to be a long-term goal. Commitment to the RGC fate requires Ath5 action, but how and when in its lineage history a competent progenitor cell advances to the RGC specification pathway is unclear. Improved methods for genetic manipulation and lineage tracing are now

Acknowledgements

We thank the members of the Klein lab for helpful discussions. Our work on mouse retina development was supported by NIH–NEI grants EY11930 and EY13523 and by the Robert A. Welch Foundation.

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