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The metabolism of poly(ADP-ribose) (PAR) is critical for genomic stability in multicellular eukaryotes. Here, we show that the failure to degrade PAR by means of disruption of the murine poly(ADP-ribose) glycohydrolase (PARG) gene unexpectedly causes early embryonic lethality and enhanced sensitivity to genotoxic stress. This lethality results from the failure to hydrolyze PAR, because PARG null embryonic day (E) 3.5 blastocysts accumulate PAR and concurrently undergo apoptosis. Moreover, embryonic trophoblast stem cell lines established from early PARG null embryos are viable only when cultured in medium containing the poly(ADP-ribose) polymerase inhibitor benzamide. Cells lacking PARG also show reduced growth, accumulation of PAR, and increased sensitivity to cytotoxicity induced by N-methyl-N′-nitro-N-nitrosoguanidine and menadione after benzamide withdrawal. These results provide compelling evidence that the failure to degrade PAR has deleterious consequences. Further, they define a role for PARG in embryonic development and a protective role in the response to genotoxic stress.

The earliest cell fate decision in the mammalian embryo separates the extra-embryonic trophoblast lineage, which forms the fetal portion of the placenta, from the embryonic cell lineages. The body plan of the embryo proper is established only later at gastrulation, when the pluripotent epiblast gives rise to the germ layers ectoderm, mesoderm and endoderm. Here we show that the T-box gene Eomesodermin 1 performs essential functions in both trophoblast development and gastrulation. Mouse embryos lacking Eomesodermin arrest at the blastocyst stage. Mutant trophoectoderm does not differentiate into trophoblast, indicating that Eomesodermin may be required for the development of trophoblast stem cells 2 . In the embryo proper, Eomesodermin is essential for mesoderm formation. Although the specification of the anterior–posterior axis and the initial response to mesoderm-inducing signals is intact in mutant epiblasts, the prospective mesodermal cells are not recruited into the primitive streak. Our results indicate that Eomesodermin defines a conserved molecular pathway controlling the morphogenetic movements of germ layer formation and has acquired a new function in mammals in the differentiation of trophoblast.

We investigated the disturbance effects of offshore windfarm construction on harbour porpoises Phocoena phocoena using acoustic porpoise monitoring data and noise measurements during construction of the first 7 large-scale offshore wind farms in the German Bight between 2010 and 2013. At 6 wind farms, active noise mitigation systems (NMS) were applied during most piling events, and 1 was constructed without. Based on generalized additive modelling analyses, we describe a clear gradient in the decline of porpoise detections after piling, depending on noise level and distance to piling. Declines were found at sound levels exceeding 143 dB re 1 μPa²s (the sound exposure level exceeded during 5% of piling time, SEL05) and up to 17 km from piling. When only considering piling events with NMS, the maximum effect distance was 14 km. Compared to 24–48 h before piling, porpoise detections declined more strongly during unmitigated piling events at all distances: at 10–15 km declines were around 50% during piling without NMS, but only 17% when NMS were applied. Within the vicinity (up to about 2 km) of the construction site, porpoise detections declined several hours before the start of piling and were reduced for about 1–2 d after piling, while at the maximum effect distance, avoidance was only found during the hours of piling. The application of first generation NMS thus reduced the effect range of pile driving and led to a lower decline of porpoise detections over all distances. However, NMS were still under development and did not always work with equal efficiency. As NMS have further developed since, future investigations are expected to show additional reduction of disturbance effects.