Dynamic Rewiring of the Drosophila Retinal Determination Network Switches Its Function from Selector to Differentiation

Abstract

Organ development is directed by selector gene networks. Eye development in the fruit fly Drosophila melanogaster is driven by the highly conserved selector gene network referred to as the “retinal determination gene network,” composed of approximately 20 factors, whose core comprises twin of eyeless (toy), eyeless (ey), sine oculis (so), dachshund (dac), and eyes absent (eya). These genes encode transcriptional regulators that are each necessary for normal eye development, and sufficient to direct ectopic eye development when misexpressed. While it is well documented that the downstream genes so, eya, and dac are necessary not only during early growth and determination stages but also during the differentiation phase of retinal development, it remains unknown how the retinal determination gene network terminates its functions in determination and begins to promote differentiation. Here, we identify a switch in the regulation of ey by the downstream retinal determination genes, which is essential for the transition from determination to differentiation. We found that central to the transition is a switch from positive regulation of ey transcription to negative regulation and that both types of regulation require so. Our results suggest a model in which the retinal determination gene network is rewired to end the growth and determination stage of eye development and trigger terminal differentiation. We conclude that changes in the regulatory relationships among members of the retinal determination gene network are a driving force for key transitions in retinal development.

Antagonistic regulation of the second mitotic wave by Eyes absent-Sine oculis and Combgap coordinates proliferation and specification in the Drosophila retina

“…One emerging hypothesis is that Eya-So switches between activating and repressing its transcriptional targets, but the co-factors that drive these shifts and their relevance to proliferation are unknown. Specifically, So promotes ey transcription in retinal precursors, while Eya-So inhibits its expression in differentiating cells (Atkins et al, 2013). Similarly, Eya-So activates stg expression anterior to the MF, but not when cells arrest in G 1 (Jemc and Rebay, 2007).…”

“…That Eya is a transcriptional coactivator for So is well established (Ohto et al, 1999;Silver et al, 2003;Xu et al, 1997), and recent work has shown that Eya-So directly represses ey expression in differentiating cells posterior to the MF (Atkins et al, 2013). Extrapolating to the context of the SMW, Eya-So could limit proliferation by either activating the expression of negative regulators or repressing the expression of positive regulators, with different outputs presumably determined by its co-factors.…”

“…Dac interferes with the pro-proliferative transcriptional complexes to terminate mitogenic activity and permit differentiation, while Eya and So, operating as a bipartite transcription factor, take control of the cell cycle by activating a burst of string (stg) transcription that forces cells into M phase and prepares them for coordinated G 1 arrest (Brás-Pereira et al, 2015;Jemc and Rebay, 2007;Pignoni et al, 1997). Shortly thereafter, Eya-So first cooperates with Ey to activate atonal expression and initiate neuronal specification and then directly represses ey transcription to stabilize the suppression of the earlier proliferation program in the differentiating cells (Atkins et al, 2013;Zhang et al, 2006;Zhou et al, 2014).…”

MicroRNA-552 promotes tumor cell proliferation and migration by directly targeting DACH1 via the Wnt/β-catenin signaling pathway in colorectal cancer

“…As a cancer suppress gene, DACH1 is a crucial member of the Retinal Determination Gene Network (25). Generally, it has been demonstrated to be downregulated in a wide number of tumors, such as breast, endometrial and prostate cancer (19).…”

DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling

“…RDGN is required for drosophila eye specification [1]. Through gene-specific recruitment of coactivator or corepressor that control precursor cell proliferation and survival, mamalian homologues, DACH1/SIX1/EYA network also determines the development of many organs, including lung [2, 3].…”