Abstract: The ER-to-Golgi transport pathway is required by all cells. Our findings here reveal a surprising tissue-specific variation in dependence on SEC23B for maintenance of the secretion pathway, and suggest that murine SEC23B is particularly important for the COPII-mediated ER exit of highly abundant cargo in many tissues that specialize in protein secretion. The contrast between the species may be explained by a potential phenotypic difference between complete deficiency in mice and the residual activity observed in humans, or, alternatively, by evolutionary differences between the relative contributions of SEC23A and SEC23B across tissues. Apoptosis induced by deficiency in protein export from the ER could play a previously unappreciated role in the pathogenesis of pancreatitis. In the pancreas of SEC23B-deficient mice, defects occur in exocrine tissues that secrete digestive enzymes, as well as in endocrine tissues that secrete protein hormones, including insulin and glucagon. Endocrine and exocrine progenitor cells in the early SEC23B-deficient embryonic pancreas are normal, suggesting that abnormalities resulting in the pancreatic phenotype arise after cell fate determination. In normal exocrine pancreatic cells, digestive enzymes are stored in numerous zymogen granules after they move out of the Golgi. However, in SEC23B-deficient pancreas, exocrine cells are completely devoid of zymogen granules, and the ER becomes severely distended as a result of accumulation of proteins in the lumen ( Fig. P1 B ). Similar ultrastructural changes are also observed in other affected tissues such as the salivary glands, but not in unaffected tissues, such as the liver. Accumulation of proteins in the ER lumen activates the proapoptotic pathway of the unfolded protein response, suggesting a central role for apoptosis in the degeneration of these tissues in SEC23B-deficient embryos. The affected tissues all express relatively high levels of SEC23B compared with unaffected tissues and to the levels of SEC23A. Why do mutations in different paralogues of the COPII components result in these distinct but limited phenotypes? Such differences could result from distinct functional activities exerted by each paralogue, different temporal and/or spatial expression patterns, both of these, or unique features of the specific human mutations. Only missense mutations have been identified in CLSD, and all reported patients with CDAII retain at least one missense allele, suggesting that complete deficiencies of SEC23A or SEC23B may result in more severe phenotypes. We found that SEC23B-deficient mice survive to term, but die shortly after birth, suggesting that SEC23A alone can support major biological functions during mouse embryogenesis. In contrast to humans with CDAII, mice completely deficient for SEC23B are born with no apparent anemia phenotype, but show degeneration of specific secretory tissues, including the pancreas and the salivary, gastric, intestinal, and nasal glands ( Fig. P1 A ). Two distinct human genetic disorders have been associated with defects in SEC23 paralogues. Craniolenticulosutural dysplasia (CLSD) is characterized by craniofacial and skeletal malformation caused by homozygosity for one of two missense mutations in SEC23A ( 2 ). One mutation has been shown to interfere with the recruitment of SEC13–SEC31 to the site of vesicle formation, blocking COPII coat assembly and resulting in accumulation of cargo proteins in the ER lumen ( 3 ). Skin fibroblasts from patients with CLSD exhibit defects in collagen secretion. In contrast, mutations in SEC23B cause congenital dyserythropoietic anemia type II (CDAII) ( 4 , 5 ). CDAII patients exhibit moderate anemia due to ineffective erythropoiesis. A portion of erythroblasts in the bone marrow of patients with CDAII contains multiple nuclei, and aberrant glycosylation of specific red blood cell membrane proteins is observed. How SEC23B deficiency leads to these selective red blood cell defects in humans is unknown. The two basic functions of the COPII complex are capturing cargo into vesicles and mediating vesicle budding from the ER ( 1 ). Cargo recognition appears to be mediated primarily by the SEC24 subunit, which recognizes divergent export signals located in the cytosolic domain of cargo proteins. The GTP-bound form of SAR1 initiates vesicle budding by binding to the ER membrane and recruits the SEC23–SEC24 heterodimer, which in turn, recruits the outer coat, composed of SEC13–SEC31 heterotetramers, to complete the COPII coat structure. SEC23 is a GTPase-activating protein that activates the SAR1 GTPase. Conversion of SAR1-GTP to SAR1-GDP results in its dissociation from the COPII coat. After SAR1 release, SEC23 interacts with a tethering complex that is thought to facilitate the fusion of COPII vesicles with the target membrane. In eukaryotic cells, 20% to 30% of all synthesized proteins require export to the extracellular space or transport to the plasma membrane and internal organelles to exert their functions. Nearly all these cargo proteins are first synthesized in the endoplasmic reticulum (ER), processed by the ER quality-control machinery, and then transported to the Golgi complex. From the Golgi, cargo proteins are further sorted and moved to their final destinations. Proteins move from one organelle to the next in the secretion pathway in small membrane-enclosed packets called vesicles. Vesicle movement from the ER to the Golgi is controlled by coat protein complex II (COPII). COPII is composed of five core proteins: the small GTPase SAR1 and the two cytosolic protein complexes SEC23–SEC24 and SEC13–SEC31. Mammals express multiple paralogues of COPII proteins, including two paralogues each for SAR1, SEC23, and SEC31, and four paralogues for SEC24. The complexity of mammalian COPII proteins may be an evolutionary response to accommodate the heterogeneity of cargo molecules in different cell types and at different stages of development. Here, we studied the functions of the COPII proteins SEC23A and SEC23B by using mice genetically deficient for SEC23B expression. We found that SEC23A alone supports major biological functions during embryogenesis, and that mice completely deficient for SEC23B, unlike humans with SEC23B gene mutations, are not anemic but have degeneration of multiple secretory tissues.