A Hh-driven gene network controls specification, pattern and size of the Drosophila simple eyes

Abstract

SUMMARYDuring development, extracellular signaling molecules interact with intracellular gene networks to control the specification, pattern and size of organs. One such signaling molecule is Hedgehog (Hh). Hh is known to act as a morphogen, instructing different fates depending on the distance to its source. However, how Hh, when signaling across a cell field, impacts organ-specific transcriptional networks is still poorly understood. Here, we investigate this issue during the development of the Drosophila ocellar complex. The development of this sensory structure, which is composed of three simple eyes (or ocelli) located at the vertices of a triangular patch of cuticle on the dorsal head, depends on Hh signaling and on the definition of three domains: two areas of eya and so expression -the prospective anterior and posterior ocelli -and the intervening interocellar domain. Our results highlight the role of the homeodomain transcription factor engrailed (en) both as a target and as a transcriptional repressor of hh signaling in the prospective interocellar region. Furthermore, we identify a requirement for the Notch pathway in the establishment of en maintenance in a Hh-independent manner. Therefore, hh signals transiently during the specification of the interocellar domain, with en being required here for hh signaling attenuation. Computational analysis further suggests that this network design confers robustness to signaling noise and constrains phenotypic variation. In summary, using genetics and modeling we have expanded the ocellar gene network to explain how the interaction between the Hh gradient and this gene network results in the generation of stable mutually exclusive gene expression domains. In addition, we discuss some general implications our model may have in some Hh-driven gene networks.

Antero-posterior patterning of Drosophila ocelli requires an anti-repressor mechanism within the hh-pathway mediated by the Six3 gene Optix

“…1B,D). The mechanism by which this aOC-IOCpOC pattern is controlled by hh has recently been investigated (Aguilar-Hidalgo et al, 2013) and relies on the differential activation by the Hh signaling pathway of two Hh target genes: eya and the homeobox transcription factor engrailed (en). Hh first activates eya throughout the OCx region; then, en is turned on in a more restricted domain, which results in the attenuation of the Hh signaling pathway and the concomitant loss of eya from these cells.…”

“…Thus, the central region, expressing en and devoid of eya, becomes the IOC, whereas the remaining flanking eya-expressing domains become the retina-producing OC (Aguilar-Hidalgo et al, 2013).…”

“…Previous work has shown that en acts as a hh activator during embryo segmentation and in wing discs (Lee et al, 1992;Mohler and Vani, 1992;Simmonds et al, 1995;Tabata et al, 1995). However, during the development of the OCx, the initiation of en expression is triggered by hh, placing en downstream of hh during early ocellar development (Aguilar-Hidalgo et al, 2013).…”

Size and shape—integration of morphometrics, mathematical modelling, developmental and evolutionary biology

“…Population level variation in teeth morphology and tooth type differences in seals have been translated into mathematical models to disentangle the stages of development and the respective signaling changes responsible for the observed shape changes (Salazar-Ciudad and Jernvall 2010). In Drosophila, computational models exist that explain patterning of the dorsal head region (Aguilar-Hidalgo et al 2013) and growth control in the wing imaginal disc (Wartlick et al 2011). …”

Inference of Genome-Scale Gene Regulatory Networks: Are There Differences in Biological and Clinical Validations?

“…Gene regulatory networks (GRNs) provide a framework for representing condition and disease-specific interactions. For this reason, such networks are playing an increasingly important role in biology and medicine and translational applications derived from these [9][10][11][12][13][14][15][16][17][18]. Despite the importance of gene regulatory networks and their ample application opportunities, there are still many questions that are either unanswered or misunderstood that present serious obstacles to basic and translational research.…”