Position dependent responses to discontinuities in the retinal determination network

Abstract

Summary The development of any cell and/or tissue is dependent upon interconnections between several signaling pathways and myriad transcription factors. It is becoming more apparent that these inputs are best studied, not as individual components, but rather as elements of a gene regulatory network. Over the last decade several networks governing the specification of single cells, individual organs and entire stages of development have been described. The current incarnations of these networks are the products of the continual addition of newly discovered genetic, molecular and biochemical interactions. However, as currently envisaged, network diagrams may not sufficiently describe the spatial and temporal dynamics that underlie developmental processes. We have conducted a developmental analysis of a sub circuit of the Drosophila retinal determination network. This sub circuit is comprised of three genes, two (sine oculis and dachshund) of which code for DNA binding proteins and one (eyes absent) that encodes a transcriptional co-activator. We demonstrate here that the nature of the regulatory relationships that exist between these three genes changes as retinal development progresses. We also demonstrate that the response of the tissue to the loss of any of these three RD genes is dependent upon the position of the mutant cells within the eye field. Depending upon its location, mutant tissue will either overproliferate itself or will signal to surrounding cells instructing them to propagate and compensate for the eventual loss through apoptosis of the mutant clone. Taken together these results suggest that the complexities of development are best appreciated when spatial and temporal information is incorporated when describing gene regulatory networks.

The Retinal Determination Gene eyes absent Is Regulated by the EGF Receptor Pathway Throughout Development in Drosophila

“…Instead, we observed rather patchy ectopic dac expression in the posterior-most region of the eye disc ( Figure 6D, yellow asterisks). The upregulation of dac in response to the loss of so in the most posterior sections of the retina is consistent with our previous findings that normally So can function to repress dac in this region of the developing eye (Salzer and Kumar 2009). …”

“…However in the very posterior regions of the tissue this relationship changes and So represses dac through partnership with a co-repressor. And at the margin of the eye disc there is feedback stability among all three members of this RD subcircuit (Salzer and Kumar 2009). Interestingly, based on our data in the embryo, it appears that a feedback loop exists between dac and eya in this developmental context as well as in the margin of the eye disc.…”

“…Additionally, Dac and Eya themselves have been shown to form a biochemical complex in vitro though more recent work suggests that formation of this complex might not be necessary for eye development (Chen et al 1997a;Tavsanli et al 2004). In the eye disc, the So-Eya-Dac subcircuit is flexible and the regulatory relationships change in a position dependent manner (Salzer and Kumar 2009). In most regions of the eye imaginal disc So and Eya participate in their canonical positive regulatory role with respect to dac.…”

“…Instead we observe a complete loss or severe downregulation of dac expression within aop clones (Figure 7, M-P arrowhead). As distinct regulatory relationships exist among the So-Eya-Dac subcircuit within different spatial regions of the eye field (Salzer and Kumar 2009) and since dac genetically interacts with the EGFR signaling cascade (Mardon et al 1994), the loss of dac expression in aop clones is likely the result of the combined activities of the EGFR pathway and the So-Eya complex.…”

“…Complicating our understanding of this network is that all of the interactions described to date do not necessarily occur uniformly throughout the eye. Instead, the functioning of the network seems to be influenced by spatial and temporal considerations (Salzer and Kumar 2009). …”