Notch-dependent Fizzy-related/Hec1/Cdh1 expression is required for the mitotic-to-endocycle transition in Drosophila follicle cells.

AbstractDuring Drosophila oogenesis, Notch function regulates the transition from mitotic cell cycle to endocycle in follicle cells at stage 6 [1, 2]. Loss of either Notch function or its ligand Delta (Dl) disrupts the normal transition; this disruption causes mitotic cycling to continue and leads to an overproliferation phenotype [1, 2]. In this context, the only known cell cycle component that responds to the Notch pathway is String/Cdc25 (Stg), a G2/M cell cycle regulator [1]. We found that prolonged expression of string is not sufficient to keep cells efficiently in mitotic cell cycle past stage 6, suggesting that Notch also regulates other cell cycle components in the transition. By using an expression screen, we found such a component: Fizzy-related/Hec1/Cdh1 (Fzr), a WD40 repeat protein. Fzr regulates the anaphase-promoting complex/cyclosome (APC/C) and is expressed at the mitotic-to-endocycle transition in a Notch-dependent manner. Mutant clones of Fzr revealed that Fzr is dispensable for mitosis but essential for endocycles. Unlike in Notch clones, in Fzr mutant cells mitotic markers are absent past stage 6. Only a combined reduction of Fzr and ectopic Stg expression prolongs mitotic cycles in follicle cells, suggesting that these two cell cycle regulators, Fzr and Stg, are important mediators of the Notch pathway in the mitotic-to-endocycle transition

Tramtrack Is Genetically Upstream of Genes Controlling Tracheal Tube Size in Drosophila

The Drosophila transcription factor Tramtrack (Ttk) is involved in a wide range of developmental decisions, ranging from early embryonic patterning to differentiation processes in organogenesis. Given the wide spectrum of functions and pleiotropic effects that hinder a comprehensive characterisation, many of the tissue specific functions of this transcription factor are only poorly understood. We recently discovered multiple roles of Ttk in the development of the tracheal system on the morphogenetic level. Here, we sought to identify some of the underlying genetic components that are responsible for the tracheal phenotypes of Ttk mutants. We therefore profiled gene expression changes after Ttk loss- and gain-of-function in whole embryos and cell populations enriched for tracheal cells. The analysis of the transcriptomes revealed widespread changes in gene expression. Interestingly, one of the most prominent gene classes that showed significant opposing responses to loss- and gain-of-function was annotated with functions in chitin metabolism, along with additional genes that are linked to cellular responses, which are impaired in ttk mutants. The expression changes of these genes were validated by quantitative real-time PCR and further functional analysis of these candidate genes and other genes also expected to control tracheal tube size revealed at least a partial explanation of Ttk's role in tube size regulation. The computational analysis of our tissue-specific gene expression data highlighted the sensitivity of the approach and revealed an interesting set of novel putatively tracheal genes

Extracellular Matrix Protection Factor-1 Treatment in a Rat Model of Osteoarthritis Slows the Progress of Cartilage and Bone Destruction Associated with the Pathology

Osteoarthritis (OA) is a disease of the joints caused by an imbalance between extracellular matrix destruction and production. We have developed an innovative disease modifying therapeutic technology to treat OA. Extracellular matrix protection factor (ECPF-1) is a novel, safe and effective intra-articular injection effective in alleviating tissue pathology associated with OA. Knees of rats in an OA model were treated with ECPF-1 peptide or BMP-7 protein as a control because BMP-7 has been shown to be chondroprotective in a rabbit model of OA. Micro computed tomography (uCT) indicates the amount of bone volume present in the samples and the areas of mineralization. Since healthy cartilage is not normally mineralized, one would expect a low bone volume in these samples and a higher bone volume in cartilage of OA. ECPF-1 treated OA joints contained the lowest bone volume after four weekly injections of peptide. Trabecular thickness indicates the strength of the bone, and the ECPF-1 treated animals had the best trabecular thickness numbers following 4 weekly injections of peptide. This data provides critical proof of concept that ECPF-1 acts as a disease modifying therapeutic in a rat model of OA. This work was supported in part by intramural funding