The unfolded protein response in metazoan development

Eukaryotic cells respond to an overload of unfolded proteins in the endoplasmic reticulum (ER) by activating signaling pathways that are referred to as the unfolded protein response (UPR). Much UPR research has been conducted in cultured cells that exhibit no baseline UPR activity until they are challenged by ER stress initiated by chemicals or mutant proteins. At the same time, many genes that mediate UPR signaling are essential for the development of organisms ranging from Drosophila and fish to mice and humans, indicating that there is physiological ER stress that requires UPR in normally developing animal tissues. Recent studies have elucidated the tissue-specific roles of all three branches of UPR in distinct developing tissues of Drosophila, fish and mammals. As discussed in this Review, these studies not only reveal the physiological functions of the UPR pathways but also highlight a surprising degree of specificity associated with each UPR branch in development.