Meis1 regulates Foxn4 expression during retinal progenitor cell differentiation

Mohammed M Islam,Ying Li,Mengqing Xiang,Li Cai,Huijun Luo

doi:10.1242/bio.20132279

Abstract

SummaryThe transcription factor forkhead box N4 (Foxn4) is a key regulator in a variety of biological processes during development. In particular, Foxn4 plays an essential role in the genesis of horizontal and amacrine neurons from neural progenitors in the vertebrate retina. Although the functions of Foxn4 have been well established, the transcriptional regulation of Foxn4 expression during progenitor cell differentiation remains unclear. Here, we report that an evolutionarily conserved 129 bp noncoding DNA fragment (Foxn4CR4.2 or CR4.2), located ∼26 kb upstream of Foxn4 transcription start site, functions as a cis-element for Foxn4 regulation. CR4.2 directs gene expression in Foxn4-positive cells, primarily in progenitors, differentiating horizontal and amacrine cells. We further determined that the gene regulatory activity of CR4.2 is modulated by Meis1 binding motif, which is bound and activated by Meis1 transcription factor. Deletion of the Meis1 binding motif or knockdown of Meis1 expression abolishes the gene regulatory activity of CR4.2. In addition, knockdown of Meis1 expression diminishes the endogenous Foxn4 expression and affects cell lineage development. Together, we demonstrate that CR4.2 and its interacting Meis1 transcription factor play important roles in regulating Foxn4 expression during early retinogenesis. These findings provide new insights into molecular mechanisms that govern gene regulation in retinal progenitors and specific cell lineage development.

Highlights

The vertebrate retina is an excellent model to study the development of the nervous system including the cell differentiation process
forkhead box N4 (Foxn4) plays an essential role in the genesis of horizontal and amacrine neurons from neural progenitors in the vertebrate retina
We further determined that the gene regulatory activity of CR4.2 is modulated by Meis1 binding motif, which is bound and activated by Meis1 transcription factor

Summary

Introduction

The vertebrate retina is an excellent model to study the development of the nervous system including the cell differentiation process. More than 50 subtypes of retinal neurons have been identified (Masland, 2001), the vertebrate retina is mainly composed of six major types of neurons and one major type of glial cells. These seven major cell types are derived from a common pool of multipotent retinal progenitor cells (RPC) that differentiate in a conserved chronological order (Livesey and Cepko, 2001). An excellent way to gain an understanding of how these factors work together in networks is the dissection of gene regulatory elements of key transcription factors

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