Onecut1 and Onecut2 play critical roles in the development of the mouse retina.

Jillian J Goetz,Gregory M Martin,Jeffrey M Trimarchi,Rebecca Chowdhury,Alexandre H Kihara

doi:10.1371/journal.pone.0110194

Abstract

The entire repertoire of intrinsic factors that control the cell fate determination process of specific retinal neurons has yet to be fully identified. Single cell transcriptome profiling experiments of retinal progenitor cells revealed considerable gene expression heterogeneity between individual cells, especially among different classes of transcription factors. In this study, we show that two of those factors, Onecut1 and Onecut2, are expressed during mouse retinal development. Using mice that are deficient for each of these transcription factors, we further demonstrate a significant loss (∼70–80%) of horizontal cells in the absence of either of these proteins, while the other retinal cells appear at normal numbers. Microarray profiling experiments performed on knockout retinas revealed defects in horizontal cell genes as early as E14.5. Additional profiling assays showed an upregulation of several stress response genes in the adult Onecut2 knockout, suggesting that the integrity of the retina is compromised in the absence of normal numbers of horizontal cells. Interestingly, melanopsin, the gene coding for the photopigment found in photosensitive ganglion cells, was observed to be upregulated in Onecut1 deficient retinas, pointing to a possible regulatory role for Onecut1. Taken together, our data show that similar to Onecut1, Onecut2 is also necessary for the formation of normal numbers of horizontal cells in the developing retina.

Highlights

Cell fate determination is an intricate process that is controlled by combinations of genes, which have not yet been fully identified
The Math5 transcription factor is expressed during the early stages of mouse retina development in the lineages of many retinal cells, including photoreceptors, amacrine cells, horizontal cells, and ganglion cells [20]
To identify genes involved in the cell fate determination process of early-born retinal neurons, we isolated single Math5+ progenitor cells and identified genes that were strongly correlated with Math5 expression in these cells [16]

Summary

Introduction

Cell fate determination is an intricate process that is controlled by combinations of genes, which have not yet been fully identified. A better understanding of how cellular diversity arises in vertebrates can help us comprehend precisely how cells become specialized to perform specific functions within a complex tissue. Developing neural progenitors must integrate extrinsic signals from their environment and neighboring cells, as well as intrinsic cues (usually in the form of transcription factors), in order to make appropriate cell fate determinations. A stochastic or probabilistic model of cell-fate determination proposes a more fluid development, wherein the dynamic nature of intrinsic and extrinsic signals lead to changing probabilities of a progenitor cell generating various different cell types [3,5]. Evidence for theories of neurogenesis exists in different model systems [5,6], recent studies in zebrafish suggest that stochastic probabilities play a role in the cell fate determination of the developing retina [3]

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