Functional domains of ERdj4 include a J domain that associates with BiP and a glycine/phenylalanine-rich region that likely interacts with unfolded or misfolded substrates. ERdj4 facilitates the removal of newly synthesized unfolded/misfolded protein substrates from the ER lumen by associating with the ERAD machinery via a poorly understood mechanism. Although ERdj4 expression is highly upregulated in response to ER stress, recent studies revealed an unanticipated role for ERdj4 in growth, development and metabolism. Hypomorphic expression of ERdj4 in mice resulted in perinatal lethality associated with growth restriction and hypoglycemia, while surviving adult mice were glucose intolerant and hypoinsulinemic, with defects in the pancreatic b-cell secretory pathway. In the current study, we investigated the role of ERdj4 in hematopoiesis. ERdj4 gene trap mice exhibited abnormal numbers of myeloid, erythroid and B lymphoid cells in the bone marrow. Further analyses of B cell development revealed an intrinsic defect that reduced survival of large and small pre-B, and immature B cells in ERdj4gt/gt mice. Consistent with these findings, mature recirculating B cells were decreased in the bone marrow and spleen of ERdj4gt/gt mice. Unexpectedly, basal immunoglobulins were increased in ERdj4gt/gt mice in association with enhanced class switch recombination in vitro; however, ERdj4gt/gt mice failed to mount a specific antibody response to T cell-dependent antigen. Collectively, these data indicate that the chaperone activity of ERdj4 is required for normal development of hematopoietic lineages and function of B lymphocytes. ERdj4 is regulated by the UPR to facilitate the removal of unfolded/misfolded proteins from the ER lumen for degradation by the proteasome. Although ERdj4 is Terazosin HCl clearly required for ERAD of specific terminally misfolded proteins, Lenalidomide hemihydrate emerging evidence suggests that it may also play a more general role in productive protein folding in highly metabolic cells. Mice deficient in ERdj4 exhibit constitutive ER stress associated with defects in growth, development and metabolism.