A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis.

Ewing's sarcoma, a malignant bone tumor of children and young adults, is a member of the small-round-blue-cell tumor family. Ewing's sarcoma family tumors (ESFTs), which include peripheral primitive neuroectodermal tumors (PNETs), are characterized by chromosomal translocations that generate fusions between the EWS gene and ETS-family transcription factors, most commonly FLI1. The EWS-FLI1 fusion oncoprotein represents an attractive therapeutic target for treatment of Ewing's sarcoma. The cell of origin of ESFT and the molecular mechanisms by which EWS-FLI1 mediates tumorigenesis remain unknown, and few animal models of Ewing's sarcoma exist. Here, we report the use of zebrafish as a vertebrate model of EWS-FLI1 function and tumorigenesis. Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly resembling that of human Ewing's sarcoma. The incidence of tumors increased in a p53 mutant background, suggesting that the p53 pathway suppresses EWS-FLI1-driven tumorigenesis. Gene expression profiling of the zebrafish tumors defined a set of genes that might be regulated by EWS-FLI1, including the zebrafish ortholog of a crucial EWS-FLI1 target gene in humans. Stable zebrafish transgenic lines expressing EWS-FLI1 under the control of the heat-shock promoter exhibit altered embryonic development and defective convergence and extension, suggesting that EWS-FLI1 interacts with conserved developmental pathways. These results indicate that functional targets of EWS-FLI1 that mediate tumorigenesis are conserved from zebrafish to human and provide a novel context in which to study the function of this fusion oncogene.

Conception date affects litter type and foetal sex ratio in female moose in Estonia.

1. The Trivers-Willard model of optimal sex ratios predicts that in polygynous species mothers in better condition should produce more male than female offspring. However, empirical support for this hypothesis in mammals and especially ungulates has been equivocal. This may be because the fitness of mothers has been defined in different ways, reflecting morphological, physiological or behavioural measures of condition. In addition, factors other than maternal condition can influence a mother's fitness. Given that recent studies of wild ungulates have demonstrated the importance of the timing of conception and birth on offspring fitness, litters conceived at different stages of the rut might be expected to exhibit differences in types and embryonic sex ratio. 2. Based on a 6-year survey of the reproductive tracts of female moose harvested in Estonia, we investigated the effect of conception date on the types of litters produced and on the foetal sex ratio. 3. There was a clear relationship between conception date and litter characteristics. Overall, earlier conceived litters were more likely than those conceived late to contain multiple embryos and a high proportion of males. However, while foetal sex ratio varied nonlinearly with conception date in yearlings and subadults, no relationship was found in adults. 4. We conclude that female moose adjust foetal sex ratio and litter type/size depending on their age and the date of conception, and that these adjustments are in accordance with the Trivers-Willard hypothesis if females that conceive earlier are in better condition.

CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits.

Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element-binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K(+) channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.

The influence of DeltaFosB in the nucleus accumbens on natural reward-related behavior.

The transcription factor deltaFosB (DeltaFosB), induced in nucleus accumbens (NAc) by chronic exposure to drugs of abuse, has been shown to mediate sensitized responses to these drugs. However, less is known about a role for DeltaFosB in regulating responses to natural rewards. Here, we demonstrate that two powerful natural reward behaviors, sucrose drinking and sexual behavior, increase levels of DeltaFosB in the NAc. We then use viral-mediated gene transfer to study how such DeltaFosB induction influences behavioral responses to these natural rewards. We demonstrate that overexpression of DeltaFosB in the NAc increases sucrose intake and promotes aspects of sexual behavior. In addition, we show that animals with previous sexual experience, which exhibit increased DeltaFosB levels, also show an increase in sucrose consumption. This work suggests that DeltaFosB is not only induced in the NAc by drugs of abuse, but also by natural rewarding stimuli. Additionally, our findings show that chronic exposure to stimuli that induce DeltaFosB in the NAc can increase consumption of other natural rewards.

Climatic effects on life-history traits of moose in Estonia.

Weather variables can influence life-history traits of ungulates. In this study, we assessed the suitability of regional climate indices including the NAO and two measures of local climate-the maximal extent of ice on the Baltic Sea (MIE) and absolute values of its annual deviations from the multi-year mean (VMIE)-to examine how density-independent processes influence moose body size and fecundity. We predicted that both winter severity (large values of MIE) and variability (large values of VMIE) depress moose traits (e.g., severe winters increase energy expenditure because of large snow depth or low temperatures, while the warmer than average winters may impose greater energetic demands on thermoregulation due to wet and windy weather, or may have indirect negative effects on summer foraging conditions). We estimated direct, delayed (lag) and cumulative effects of each climate measure. Both MIE and VMIE negatively affected jawbone length, with the effect size varying between the respective climatic indices and among age classes. In contrast to results obtained using local climatic variables, the NAO index had no significant effect on jawbone length. The probability of multiple ovulation was negatively influenced by direct effects of VMIE and delayed effects of MIE and NAO. We conclude that MIE and VMIE capture different aspects of the local climate and that these indices can be used in parallel as determinants of growth and fecundity of northern ungulates in coastal regions of the Baltic Sea.