Nutritional and metabolic control of germ cell fate through O‐GlcNAc regulation

Fate determination of primordial germ cells (PGCs) is regulated in a multi‐layered manner, involving signaling pathways, epigenetic mechanisms, and transcriptional control. Chemical modification of macromolecules, including epigenetics, is expected to be closely related with metabolic mechanisms but the detailed molecular machinery linking these two layers remains poorly understood. Here, we show that the hexosamine biosynthetic pathway controls PGC fate determination via O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) modification. Consistent with this model, reduction of carbohydrate metabolism via a maternal ketogenic diet that decreases O‐GlcNAcylation levels causes repression of PGC formation in vivo . Moreover, maternal ketogenic diet intake until mid‐gestation affects the number of ovarian germ cells in newborn pups. Taken together, we show that nutritional and metabolic mechanisms play a previously unappreciated role in PGC fate determination. image The hexosamine biosynthetic pathway and protein O‐GlcNAcylation play a role in PGC specification. Reduction of carbohydrate metabolism via a maternal ketogenic diet also controls fetal PGC development through this pathway, suggesting the possibility that nutritional status in early pregnancy regulates fetal germ cell formation and differentiation. Glucose regulates PGC formation via the hexosamine biosynthetic pathway and protein O‐GlcNAcylation in vitro . Suppression of carbohydrate metabolism and O‐GlcNAcylation in vivo by Ogt‐cKO or ketogenic diets reduces PGC formation and germ cell development in mice.