Role of the circadian clock in the statistics of locomotor activity in Drosophila.

In many animals the circadian rhythm of locomotor activity is controlled by an endogenous circadian clock. Using custom made housing and video tracking software in order to obtain high spatial and temporal resolution, we studied the statistical properties of the locomotor activity of wild type and two clock mutants of Drosophila melanogaster. We show here that the distributions of activity and quiescence bouts for the clock mutants in light-dark conditions (LD) are very different from the distributions obtained when there are no external cues from the environment (DD). In the wild type these distributions are very similar, showing that the clock controls this aspect of behavior in both regimes (LD and DD). Furthermore, the distributions are very similar to those reported for Wistar rats. For the timing of events we also observe important differences, quantified by how the event rate distributions scale for increasing time windows. We find that for the wild type these distributions can be rescaled by the same function in DD as in LD. Interestingly, the same function has been shown to rescale the rate distributions in Wistar rats. On the other hand, for the clock mutants it is not possible to rescale the rate distributions, which might indicate that the extent of circadian control depends on the statistical properties of activity and quiescence.

The Underlying Genetics of Drosophila Circadian Behaviors.

Life is shaped by circadian clocks. This review focuses on how behavioral genetics in the fruit fly unveiled what is known today about circadian physiology. We will briefly summarize basic properties of the clock and focus on some clock-controlled behaviors to highlight how communication between central and peripheral oscillators defines their properties.

Snail1 suppresses TGF-beta-induced apoptosis and is sufficient to trigger EMT in hepatocytes.

Although TGF-ß suppresses early stages of tumour development, it later contributes to tumour progression when cells become resistant to its suppressive effects. In addition to circumventing TGF-ß-induced growth arrest and apoptosis, malignant tumour cells become capable of undergoing epithelial-to-mesenchymal transition (EMT), favouring invasion and metastasis. Therefore, defining the mechanisms that allow cancer cells to escape from the suppressive effects of TGF-ß is fundamental to understand tumour progression and to design specific therapies. Here, we have examined the role of Snail1 as a suppressor of TGF-ß-induced apoptosis in murine non-transformed hepatocytes, rat and human hepatocarcinoma cell lines and transgenic mice. We show that Snail1 confers resistance to TGF-ß-induced cell death and that it is sufficient to induce EMT in adult hepatocytes, cells otherwise refractory to this transition upon exposure to TGF-ß. Furthermore, we show that Snail1 silencing prevents EMT and restores the cell death response induced by TGF-ß. As Snail1 is a known target of TGF-ß signalling, our data indicate that Snail1 might transduce the tumour-promoting effects of TGF-ß, namely the EMT concomitant with the resistance to cell death.

ENA/VASP downregulation triggers cell death by impairing axonal maintenance in hippocampal neurons.

Neurodegenerative diseases encompass a broad variety of motor and cognitive disorders that are accompanied by death of specific neuronal populations or brain regions. Cellular and molecular mechanisms underlying these complex disorders remain largely unknown. In a previous work we searched for novel Drosophila genes relevant for neurodegeneration and singled out enabled (ena), which encodes a protein involved in cytoskeleton remodeling. To extend our understanding on the mechanisms of ENA-triggered degeneration we now investigated the effect of silencing ena ortholog genes in mouse hippocampal neurons. We found that ENA/VASP downregulation led to neurite retraction and concomitant neuronal cell death through an apoptotic pathway. Remarkably, this retraction initially affected the axonal structure, showing no effect on dendrites. Reduction in ENA/VASP levels blocked the neuritogenic effect of a specific RhoA kinase (ROCK) inhibitor, thus suggesting that these proteins could participate in the Rho-signaling pathway. Altogether these observations demonstrate that ENA/VASP proteins are implicated in the establishment and maintenance of the axonal structure and that a change on their expression levels triggers neuronal degeneration.