Under adverse conditions, Caenorhabditis elegans enters a diapause stage called the dauer larva. External cues signal the nuclear hormone receptor DAF-12, the activity of which is regulated by its ligands: dafachronic acids (DAs). DAs are synthesized from cholesterol, with the last synthesis step requiring NADPH, and their absence stimulates dauer formation. Here we show that NADPH levels determine dauer formation in a regulatory mechanism involving key carbohydrate and redox metabolic enzymes. Elevated trehalose biosynthesis diverts glucose-6-phosphate from the pentose phosphate pathway, which is the major source of cellular NADPH. This enhances dauer formation due to the decrease in the DA level. Moreover, DAF-12, in cooperation with DAF-16/FoxO, induces negative feedback of DA synthesis via activation of the trehalose-producing enzymes TPS-1/2 and inhibition of the NADPH-producing enzyme IDH-1. Thus, the dauer developmental decision is controlled by integration of the metabolic flux of carbohydrates and cellular redox potential.

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Sheep are among the earliest domesticated livestock species, with a wide variety of breeds present today. However, it remains unclear how far back this breed diversity goes, with formal documentation only dating back a few centuries. North European short tail breeds are often assumed to be among the oldest domestic sheep populations, even thought to represent relicts of the earliest sheep expansions during the Neolithic period reaching Scandinavia less than 6000 years ago. This study sequenced the genomes (up to 11.6X) of five sheep remains from the Baltic islands of Gotland and Åland, dating from Late Neolithic (~4100 calBP) to historical times (~1600 CE). Our findings indicate that these ancient sheep already possessed the genetic characteristics of modern North European short tail breeds, suggesting a long-term continuity of this breed type in the Baltic Sea region. Despite the wide temporal spread, population genetic analyses show high levels of affinity between the ancient genomes and they exhibit higher genetic diversity compared to modern breeds, implying a loss of diversity in recent centuries associated with breed formation. Finally, we see a potential signature of an even earlier, genetically different form of sheep in Scandinavia as these samples do not represent the first sheep in Northern Europe. Our results shed light on the development of breeds in Northern Europe specifically and the development of genetic diversity in sheep breeds and their expansion from the domestication center in general.

Recovery from the quiescent developmental stage called dauer is an essential process in C. elegans and provides an excellent model to understand how metabolic transitions contribute to developmental plasticity. We here show that the depletion of sterol-binding proteins SCL-12 and SCL-13 is the key change in the C. elegans proteome in early dauer recovery. This process releases a cholesterol store that is sequestered in the gut lumen during the dauer state to facilitate the transition into reproductive development. First, the stored cholesterol undergoes endocytosis into the lysosomes of the intestinal cells, where it activates mTOR to promote protein synthesis and growth. Second, it is used for the production of dafachronic acids that switch metabolic programs at the transcriptional level. These processes are essential for population fitness and survival, as loss of SCL-12 and SCL-13, depletion of sterols, and loss of mTOR precludes quiescence exit, ultimately leading to the expiration of the entire population.