The vertebrate yolk sac: evolutionary origins and current advances in in vitro models

A key innovation in the evolutionary history of animals was the emergence of embryonic yolk, maternal nutrient deposits in the egg primarily composed of lipids and vitellogenin proteins. To contain and utilise yolk as a nutritional resource, many species have co-opted extra-embryonic tissue, named the extra-embryonic endoderm, to form a yolk sac. Extra-embryonic endoderm is believed to be conserved across vertebrate evolution, although its form and function have varied greatly over the past 500 million years. The yolk sac retains an essential role in nutrient transport, even in mammalian species that subsequently lost their yolk, and has also evolved additional functions in signalling and embryonic patterning. In this Review, we summarise our current understanding of vertebrate extra-embryonic endoderm evolution and diversity. We synthesise recent findings in reptiles to examine the evolution of the yolk sac and extra-embryonic endoderm in amniotes. Finally, we discuss how in vitro models can illuminate the function of this evolutionarily ancient extra-embryonic tissue, especially in the context of human development, in which yolk sac samples are extremely limited for investigation.