The effects of Hh morphogen source movement on signaling dynamics.

Morphogens of the Hh family trigger gene expression changes in receiving cells in a concentration-dependent manner to regulate their identity, proliferation, death or metabolism, depending on the tissue or organ. This variety of responses relies on a conserved signaling pathway. Its logic includes a negative-feedback loop involving the Hh receptor Ptc. Here, using experiments and computational models we study and compare the different spatial signaling profiles downstream of Hh in several developing Drosophila organs. We show that the spatial distributions of Ptc and the activator transcription factor CiA in wing, antenna and ocellus show similar features, but are markedly different from that in the compound eye. We propose that these two profile types represent two time points along the signaling dynamics, and that the interplay between the spatial displacement of the Hh source in the compound eye and the negative-feedback loop maintains the receiving cells effectively in an earlier stage of signaling. These results show how the interaction between spatial and temporal dynamics of signaling and differentiation processes may contribute to the informational versatility of the conserved Hh signaling pathway.

Control of size, fate and time by the Hh morphogen in the eyes of flies.

Molecules of the hedgehog (hh) family are involved in the specification and patterning of eyes in vertebrates and invertebrates. These organs, though, are of very different sizes, raising the question of how Hh molecules operate at such different scales. In this paper we discuss the strategies used by Hh to control the development of the two eye types in Drosophila: the large compound eye and the small ocellus. We first describe the distinct ways in which these two eyes develop and the evidence for the key role played by Hh in both; then we consider the potential for variation in the range of action of a "typical" morphogen and measure this range ("characteristic length") for Hh in different organs, including the compound eye and the ocellus. Finally, we describe how different feedback mechanisms are used to extend the Hh range of action to pattern the large and even the small eye. In the ocellus, the basic Hh signaling pathway adds to its dynamics the attenuation of its receptor as cell differentiate. This sole regulatory change can result in the decoding of the Hh gradient by receiving cells as a wave of constant speed. Therefore, in the fly ocellus, the Hh morphogen adds to its spatial patterning role a novel one: patterning along a time axis.

Dynamic Hh signalling can generate temporal information during tissue patterning.

The differentiation of tissues and organs requires that cells exchange information in space and time. Spatial information is often conveyed by morphogens: molecules that disperse across receiving cells to generate signalling gradients. Cells translate such concentration gradients into space-dependent patterns of gene expression and cellular behaviour. But could morphogen gradients also convey developmental time? Here, by investigating the developmental role of Hh on a component of the Drosophila visual system, the ocellar retina, we have discovered that ocellar cells use the non-linear gradient of Hh as a temporal cue, collectively performing the biological equivalent of a mathematical logarithmic transformation. In this way, a morphogen diffusing from a non-moving source is decoded as a wave of differentiating photoreceptors that travels at constant speed throughout the retinal epithelium.

Toward a study of gene regulatory constraints to morphological evolution of the Drosophila ocellar region.

The morphology and function of organs depend on coordinated changes in gene expression during development. These changes are controlled by transcription factors, signaling pathways, and their regulatory interactions, which are represented by gene regulatory networks (GRNs). Therefore, the structure of an organ GRN restricts the morphological and functional variations that the organ can experience-its potential morphospace. Therefore, two important questions arise when studying any GRN: what is the predicted available morphospace and what are the regulatory linkages that contribute the most to control morphological variation within this space. Here, we explore these questions by analyzing a small "three-node" GRN model that captures the Hh-driven regulatory interactions controlling a simple visual structure: the ocellar region of Drosophila. Analysis of the model predicts that random variation of model parameters results in a specific non-random distribution of morphological variants. Study of a limited sample of drosophilids and other dipterans finds a correspondence between the predicted phenotypic range and that found in nature. As an alternative to simulations, we apply Bayesian networks methods in order to identify the set of parameters with the largest contribution to morphological variation. Our results predict the potential morphological space of the ocellar complex and identify likely candidate processes to be responsible for ocellar morphological evolution using Bayesian networks. We further discuss the assumptions that the approach we have taken entails and their validity.