Elsevier

Brain Research

Volume 1192, 4 February 2008, Pages 90-98
Brain Research

Review
Regulation of retinal cell fate specification by multiple transcription factors

https://doi.org/10.1016/j.brainres.2007.04.014Get rights and content

Abstract

Retinal cell fate specification is strictly regulated by multiple transcription factors. Regarding regulation of cell proliferation and differentiation, basic helix–loop–helix (bHLH) type repressors and activators function in an antagonistic manner. Repressor-type bHLH factors maintain retinal progenitor cells, whereas activator-type bHLH factors promote neuronal cell fate determination. However, bHLH genes alone are not sufficient for acquiring proper neuronal subtype identity. Recent findings have shown that retinal cell fate specification is regulated by combinations of bHLH and homeobox genes. It is conceivable that homeobox genes confer positional identity whereas bHLH genes regulate neuronal determination and differentiation. Moreover, it has been shown that bHLH genes implicated in retinal cell fate determination regulate expression of other bHLH genes, implying that there is a complicated transcription network regulating retinal development.

Introduction

The neural retina arises from a part of the diencephalon and, because of its relatively simple structure, it has been regarded as a suitable model system to address the molecular mechanisms underlying the central nervous system development. The neural retina consists of three laminar structures: the ganglion cell layer (GCL), the inner nuclear layer (INL), and the outer nuclear layer (ONL). The neural retina contains only six types of neurons and one type of glia: retinal ganglion cells and displaced amacrine cells in the GCL; bipolar cells, amacrine cells, horizontal cells, and Müller glia in the INL; rod and cone photoreceptors in the ONL (Fig. 1B).

The neural retina is generated from common multipotent progenitors, which give rise to all types of neurons and Müller glia as shown by the lineage-tracing study using retrovirus (Turner and Cepko, 1987). Thanks to much progress in molecular biology techniques such as gene-targeting strategies and misexpression strategies using retroviral vectors, it has been shown that generation of a variety of cell types from common progenitors is strictly controlled by multiple transcription factors. It has also been postulated that as retinal development proceeds, retinal progenitors change their competence to generate a variety of retinal neurons (Harris, 1997, Cepko et al., 1996, Livesey and Cepko, 2001). In this review, we will discuss the roles of transcription factors implicated in retinal development.

Section snippets

Maintenance of retinal progenitors

At earlier stages of development, progenitors of the neural retina proliferate and expand the cell number. In mice, from around embryonic day (E) 10.5 onward, retinal progenitor cells generate retinal neurons in a temporal order conserved among many species: retinal ganglion cells first, Müller glia last. Ganglion cells, amacrine cells, cone photoreceptors, and horizontal cells differentiate at relatively early stages, while bipolar cells and rod cells are mainly generated at later stages (Fig.

Retinal ganglion cells

Retinal cell fate specification is also regulated by multiple transcription factors. Math5, a homologue of the Drosophila proneural gene atonal, is essential for the generation of retinal ganglion cells. Math5 (lacZ/+) mice, which carry lacZ at the Math5 locus, display exclusive localization of β-galactosidase to retinal ganglion cells, and targeted disruption of Math5 leads to loss of more than 80% of ganglion cells (Brown et al., 2001, Wang et al., 2001). Also, introduction of Xath5, a Xenopus

Competence of retinal progenitors

It has been shown that common progenitors give rise to different types of retinal neurons (Turner and Cepko, 1987, Cepko, 1999). It was postulated that retinal progenitors change their competence to generate different subtypes of neurons as development proceeds (Cepko et al., 1996, Livesey and Cepko, 2001). This idea is supported by several lines of evidence. In Math5-mutants, retinal ganglion cells are largely lost, while amacrine cell genesis is enhanced (Wang et al., 2001, Brown et al., 2001

Conclusions

Retinal development is regulated by multiple transcription factors. The processes of cell proliferation, neuronal determination and gliogenesis are mostly regulated by bHLH transcription factors. At early stages, Hes1 and Hes5 act to maintain retinal progenitors in an undifferentiated state and supply adequate progenitor pools. Then, neural bHLH genes start to be expressed, and retinal progenitors undergo neuronal differentiation. This process requires activity of both homeobox and bHLH genes (

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