A Defect in the Bone Marrow Microenvironment of ERdj4^GT/GT Mice Impacts B Cell Development

Abstract 3463

ERdj4 is a critical component of the unfolded protein response (UPR) that facilitates the removal of unfolded/misfolded substrates from the ER lumen for proteasomal degradation. Since previous studies have linked the UPR to B lymphopoiesis [Reimold, A.M. et al., Nature, 2001; Zhang, K. et al., JCI, 2005], we hypothesized that a deficiency in ERdj4 would impact B cell development. The ERdj4 allele was disrupted by a gene trap leading to hypomorphic expression of ERdj4 in mice homozygous for the gene trap allele (ERdj4^GT/GT). Pro-B, pre-B, immature, and mature B cell populations were significantly reduced in the bone marrow of ERdj4^GT/GT mice, which was associated with an increase in pro-B cell death. ERdj4^GT/GT donor cells transplanted into ERdj4^+/+ recipients rescued all stages of B cell development, implicating a defect in the bone marrow microenvironment. Osteoblasts support B cell development through VCAM-1, SDF-1 and IL-7 signaling [Visnjic, D. et al., Blood, 2004; Zhu, J. et al., Blood, 2007]; coincidently, the UPR is essential for osteoblast differentiation [Tohmonda, T. et al., EMBO, 2011; Wei, J. et al., J Cell Physiol, 2008]. ERdj4 deficiency in primary bone cells was associated with increased ER stress. Osteoblast-specific markers and the B cell growth factor SDF-1 was also significantly reduced in primary ERdj4^GT/GT bone cells. Importantly, osteoblasts were reduced in femur tissue sections of ERdj4^GT/GT mice. Collectively, these data suggest that the loss of ERdj4 in osteoblasts is associated with a defect in B lymphopoiesis. This research was supported by the NHLBI (HL103923 and HL086492).