The Drosophila functional Smad suppressing element fuss, a homologue of the human Skor genes, retains pro-oncogenic properties of the Ski/Sno family

Over the years Ski and Sno have been found to be involved in cancer progression e.g. in oesophageal squamous cell carcinoma, melanoma, oestrogen receptor-positive breast carcinoma, colorectal carcinoma, and leukaemia. Often, their prooncogenic features have been linked to their ability of inhibiting the anti-proliferative action of TGF-ß signalling. Recently, not only pro-oncogenic but also anti-oncogenic functions of Ski/Sno proteins have been revealed. Besides Ski and Sno, which are ubiquitously expressed other members of Ski/Sno proteins exist which show highly specific neuronal expression, the SKI Family Transcriptional Corepressors (Skor). Among others Skor1 and Skor2 are involved in the development of Purkinje neurons and a mutation of Skor1 has been found to be associated with restless legs syndrome. But neither Skor1 nor Skor2 have been reported to be involved in cancer progression. Using overexpression studies in the Drosophila eye imaginal disc, we analysed if the Drosophila Skor homologue Fuss has retained the potential to inhibit differentiation and induce increased proliferation. Fuss expressed in cells posterior to the morphogenetic furrow, impairs photoreceptor axon pathfinding and inhibits differentiation of accessory cells. However, if its expression is induced prior to eye differentiation, Fuss might inhibit the differentiating function of Dpp signalling and might maintain proliferative action of Wg signalling, which is reminiscent of the Ski/Sno protein function in cancer.

Early lineage segregation of the retinal basal glia in the Drosophila eye disc

The retinal basal glia (RBG) is a group of glia that migrates from the optic stalk into the third instar larval eye disc while the photoreceptor cells (PR) are differentiating. The RBGs are grouped into three major classes based on molecular and morphological characteristics: surface glia (SG), wrapping glia (WG) and carpet glia (CG). The SGs migrate and divide. The WGs are postmitotic and wraps PR axons. The CGs have giant nucleus and extensive membrane extension that each covers half of the eye disc. In this study, we used lineage tracing methods to determine the lineage relationships among these glia subtypes and the temporal profile of the lineage decisions for RBG development. We found that the CG lineage segregated from the other RBG very early in the embryonic stage. It has been proposed that the SGs migrate under the CG membrane, which prevented SGs from contacting with the PR axons lying above the CG membrane. Upon passing the front of the CG membrane, which is slightly behind the morphogenetic furrow that marks the front of PR differentiation, the migrating SG contact the nascent PR axon, which in turn release FGF to induce SGs’ differentiation into WG. Interestingly, we found that SGs are equally distributed apical and basal to the CG membrane, so that the apical SGs are not prevented from contacting PR axons by CG membrane. Clonal analysis reveals that the apical and basal RBG are derived from distinct lineages determined before they enter the eye disc. Moreover, the basal SG lack the competence to respond to FGFR signaling, preventing its differentiation into WG. Our findings suggest that this novel glia-to-glia differentiation is both dependent on early lineage decision and on a yet unidentified regulatory mechanism, which can provide spatiotemporal coordination of WG differentiation with the progressive differentiation of photoreceptor neurons.

Morphogenetic processes as data: Quantitative structure in the Drosophila eye imaginal disc

We can improve our understanding of biological processes through the use of computational and mathematical modeling. One such morphogenetic process (ommatidia formation in the Drosophila eye imaginal disc) provides us with an opportunity to demonstrate the power of this approach. We use a high-resolution image that catches the spatially- and temporally-dependent process of ommatidia formation in the act. This image is converted to quantitative measures and models that provide us with new information about the dynamics and geometry of this process. We approach this by addressing three computational hypotheses, and provide a publicly-available repository containing data and images for further analysis. Potential spatial patterns in the morphogenetic furrow and ommatidia are summarized, while the ommatidia cells are projected to a spherical map in order to identify higher-level spatiotemporal features. In the conclusion, we discuss the implications of our approach and findings for developmental complexity and biological theory.

Novel approach to quantitative spatial gene expression uncovers genetic stochasticity in the developing Drosophila eye

Robustness in development allows for the accumulation of neutral genetically based variation in expression, and here will be termed ‘genetic stochasticity‘. This largely neutral variation is potentially important for both evolution and complex disease phenotypes. However, it has generally only been investigated as variation exhibited in the response to large genetic perturbations. In addition, work on variation in gene expression has similarly generally been limited to being spatial, or quantitative, but because of technical restrictions not both. Here we bridge these gaps by investigating replicated quantitative spatial gene expression using rigorous statistical models, in different genotypes, sexes, and species (Drosophila melanogaster and D. simulans). Using this type of quantitative approach with developmental data allows for effective comparison among conditions, including health versus disease. We apply this approach to the morphogenetic furrow, a wave of differentiation that sweeps across the developing eye disc. Within the morphogenetic furrow, we focus on four conserved morphogens, hairy, atonal, hedgehog, and Delta. Hybridization chain reaction quantitatively measures spatial gene expression, co-staining for all four genes simultaneously and with minimal effort. We find considerable variation in the spatial expression pattern of these genes in the eye between species, genotypes, and sexes. We also find that there has been evolution of the regulatory relationship between these genes. Lastly, we show that the spatial interrelationships of these genes evolved between species in the morphogenetic furrow. This is essentially the first ‘population genetics of development’ as we are able to evaluate wild type differences in spatial and quantitative gene expression at the level of genotype, species and sex.