Temporal regulation of Ath5 gene expression during eye development

Abstract

During central nervous system development the timing of progenitor differentiation must be precisely controlled to generate the proper number and complement of neuronal cell types. Proneural basic helix-loop-helix (bHLH) transcription factors play a central role in regulating neurogenesis, and thus the timing of their expression must be regulated to ensure that they act at the appropriate developmental time. In the developing retina, the expression of the bHLH factor Ath5 is controlled by multiple signals in early retinal progenitors, although less is known about how these signals are coordinated to ensure correct spatial and temporal pattern of gene expression. Here we identify a key distal Xath5 enhancer and show that this enhancer regulates the early phase of Xath5 expression, while the proximal enhancer we previously identified acts later. The distal enhancer responds to Pax6, a key patterning factor in the optic vesicle, while FGF signaling regulates Xath5 expression through sequences outside of this region. In addition, we have identified an inhibitory element adjacent to the conserved distal enhancer region that is required to prevent premature initiation of expression in the retina. This temporal regulation of Xath5 gene expression is comparable to proneural gene regulation in Drosophila, whereby separate enhancers regulate different temporal phases of expression.

Ras-Related Nuclear Protein is required for late developmental stages of retinal cells in zebrafish eyes

“…Thus, premature cell cycle exit could cause the overexpression of ath5, which is the first expressed proneural gene that determines the fate of neural ganglion cells, resulting in high RGC production. However, in the absence of ath5, RGC proliferation would be affected (Willardsen et al, 2009). In this study, we observed that ath5 was not increased in ran-deficient embryos.…”

Onset of atonal expression in Drosophila retinal progenitors involves redundant and synergistic contributions of Ey/Pax6 and So binding sites within two distant enhancers

“…For instance, the mouse bHLH genes neurogenin1, neurogenin2, Mash1, Mash2, Math1 , and Math5 , and the Xath5 locus of Xenopus , all require Pax6 for normal expression in a number of different tissues including retina, spinal cord, and/or cerebral cortex (Blader et al, 2004; Brown et al 1998; Helms et al; 2000; Hutcheson et al; 2005; Hufnagel et al, 2007; Landsberg et al; 2005; Marquardt et al; 2001; Nakada et al, 2004; Riesenberg et al, 2009; Scardigli et al, 2001; Scardigli et al, 2003; Toresson et al, 2000; Verma-Kurvari et al, 1998; Willardsen et al, 2009). Moreover, in vitro and in vivo evidence has shown that this regulation is direct for some of these targets.…”

“…How the expression of ato , and its vertebrate ortholog Ath5 (also known as Atoh7) , is first induced has been subject of studies in fly, frog, chick and mouse, leading to the identification of several highly conserved cis regulatory elements (Hufnagel et al, 2007; Hutcheson et al, 2005; Matter-Sadzinski et al, 2001; Matter-Sadzinski et al, 2005; Skowronska-Krawczyk et al, 2004; Sun et al, 1998; Sun et al, 2003; Riesenberg et al, 2009; Tanaka-Matakatsu and Du, 2008; Willardsen et al, 2009; Zhang et al, 2006). Relatively unexplored, however, are the specific mechanisms of enhancer control, i.e.…”

Molecular Control of Retinal Ganglion Cell Specification and Differentiation

“…In zebrafish deficient for both Fgf3 and Fgf8, Atoh7 expression fails to initiate in the developing retina (Martinez-Morales et al, 2005). Indeed, FGF signaling activates Xenopus Atoh7 gene expression through its 5' regulatory sequence (Willardsen et al, 2009). FGF signaling may cooperate with Shh to coordinate the subsequent spread of RGC differentiation wave front.…”