Alignment between glioblastoma internal clock and environmental cues ameliorates survival in Drosophila.

Virtually every single living organism on Earth shows a circadian (i.e. "approximately a day") internal rhythm that is coordinated with planet rotation (i.e. 24 hours). External cues synchronize the central clock of the organism. Consequences of biological rhythm disruptions have been extensively studied on cancer. Still, mechanisms underlying these alterations, and how they favor tumor development remain largely unknown. Here, we show that glioblastoma-induced neurodegeneration also causes circadian alterations in Drosophila. Preventing neurodegeneration in all neurons by genetic means reestablishes normal biological rhythms. Interestingly, in early stages of tumor development, the central pacemaker lengthens its period, whereas in later stages this is severely disrupted. The re-adjustment of the external light:dark period to longer glioblastoma-induced internal rhythms delays glioblastoma progression and ameliorates associated deleterious effects, even after the tumor onset.

Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP.

Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk.

Circadian Gene cry Controls Tumorigenesis through Modulation of Myc Accumulation in Glioblastoma Cells.

Glioblastoma (GB) is the most frequent malignant brain tumor among adults and currently there is no effective treatment. This aggressive tumor grows fast and spreads through the brain causing death in 15 months. GB cells display a high mutation rate and generate a heterogeneous population of tumoral cells that are genetically distinct. Thus, the contribution of genes and signaling pathways relevant for GB progression is of great relevance. We used a Drosophila model of GB that reproduces the features of human GB and describe the upregulation of the circadian gene cry in GB patients and in a Drosophila GB model. We studied the contribution of cry to the expansion of GB cells and the neurodegeneration and premature death caused by GB, and we determined that cry is required for GB progression. Moreover, we determined that the PI3K pathway regulates cry expression in GB cells, and in turn, cry is necessary and sufficient to promote Myc accumulation in GB. These results contribute to understanding the mechanisms underlying GB malignancy and lethality, and describe a novel role of Cry in GB cells.

Insulin signaling mediates neurodegeneration in glioma.

Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals that in consequence, promote tumor expansion at the expense of surrounding healthy tissue. The glioblastoma is one of the most aggressive and frequent primary brain tumors. This type of glioma expands and infiltrates into the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here, we describe in a Drosophila model how glioblastoma cells produce ImpL2, an antagonist of the insulin pathway, which targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, both early symptoms of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue synapse loss and to delay the premature death caused by glioma. Therefore, signals from glioblastoma to neuron emerge as a potential field of study to prevent neurodegeneration and to develop anti-tumoral strategies.

Molecular mechanisms that change synapse number.

Synapses are the functional units of the nervous system, and their number and protein composition undergo changes over a wide time scale. These synaptic changes manifest into differential behavioural outputs and, in turn, changes in the external conditions to the individual may elicit changes in synapses. We review here publications appeared during the last 10 years in which advances on molecular and cellular mechanisms for synapse changes have been reported. We focus on synaptic changes occurring in the time range of minutes to hours, mainly.

Neurogenetics of Drosophila circadian clock: expect the unexpected.

Daily biological rhythms (i.e. circadian) are a fundamental part of animal behavior. Numerous reports have shown disruptions of the biological clock in neurodegenerative disorders and cancer. In the latter case, only recently we have gained insight into the molecular mechanisms. After 45 years of intense study of the circadian rhtythms, we find surprising similarities among species on the molecular clock that governs biological rhythms. Indeed, Drosophila is one of the most widely used models in the study of chronobiology. Recent studies in the fruit fly have revealed unpredicted roles for the clock machinery in different aspects of behavior and physiology. Not only the central pacemaker cells do have non-classical circadian functions but also circadian genes work in other cells and tissues different from central clock neurons. In this review, we summarize these new evidences. We also recapitulate the most basic features of Drosophila circadian clock, including recent data about the inputs and outputs that connect the central pacemaker with other regions of the brain. Finally, we discuss the advantages and drawbacks of using natural versus laboratory conditions.