Deletion of thebisgene results in a marked increase in the production of corticosterone that is associated with thymic atrophy in mice

Abstract

Bis (Bag3) is known to be involved in cell survival, migration, the regulating of chaperones, and protein quality control. We reported recently on the production of bis gene-deleted mice, which show early lethality within 3 wk after birth with a phenotype showing severe malnutrition and shrinkage of the thymus. In this report, we provide evidence to show that an intrinsic problem of adrenal gland is the the primary cause for the severe atrophy of the thymus in bis−/− mice. The bis−/− mice show significantly higher levels of corticosterone, but CRH and ACTH levels were considerably lower than those of wild littermates. The transcription of steroidogenic enzymes was increased in the adrenal glands of bis−/− mice, accompanied by an increase in the thickness of the zona reticularis. An analysis of thymus tissue from bis−/− mice revealed that the severe atrophy of the thymus is due to the specific loss of immature double-positive (CD4+CD8+) cortical thymocytes by apoptosis, as evidenced by immunohistochemical examination and flow cytometric analysis, which were restored by injection of an inhibitor of glucocorticoid synthesis. In vitro cultures of thymocytes with increasing doses of dexamethasone exhibited a similar degree of apoptosis between wild and bis−/− thymocytes. The corticosterone levels from fasted wild littermates were one-half those of bis−/− mice, although serum glucose levels were similar. Thus, the deletion of the bis gene resulted in the intrinsic defect in the adrenal gland, leading to a marked increase in glucocorticoid levels, probably upon starvation stress, which accounts for the massive apoptosis of the thymus.

Microbial lysate upregulates host oxytocin

“…This mouse model has highly elevated levels of corticosterone due to adrenal gland zona reticularis hyperplasia coexisting with severe thymus gland atrophy. Remarkably, the premature thymic involution in this model has been shown to be due to the increased production of adrenal gland corticosterone and not due to a direct effect of Bag3 depletion in the thymus or an impaired CRH and ACTH hypothalamic-pituitary gland negative feedback signaling (Youn et al, 2011). …”

“…By contrast, stimulation of social behavior or improving sense of well-being by enrichment of caging decreased corticosterone levels while counteracting thymus shrinkage in both mice and rats (Abou-Ismail and Mahboub, 2011; Seetharaman et al, 2016; Van Loo et al, 2004). A study in genetically engineered mice has provided direct evidence linking thymus gland size and function with corticosterone (Youn et al, 2011). Specifically, Youn et al (2011) have used mice that were deficient in Bag3, a multifunctional molecule involved in cell survival, migration, chaperone regulation, and cellular protein metabolism.…”

“…A study in genetically engineered mice has provided direct evidence linking thymus gland size and function with corticosterone (Youn et al, 2011). Specifically, Youn et al (2011) have used mice that were deficient in Bag3, a multifunctional molecule involved in cell survival, migration, chaperone regulation, and cellular protein metabolism. This mouse model has highly elevated levels of corticosterone due to adrenal gland zona reticularis hyperplasia coexisting with severe thymus gland atrophy.…”

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

“…We previously demonstrated that the deletion of the Bis gene (also known as Bag3) in mice results in growth retardation and early lethality with serious metabolic deterioration [24,25], suggesting that BIS is critical for postnatal growth and survival. In contrast to Bis-knockout mice, the growth and reproduction of Bis -heterozygote ([Bis +/− ]; BIS-HT) mice appeared to be normal.…”

Expression of Bis in the mouse gastrointestinal system

“…However, even though z-disk disruption was also observed in our model, massive apoptotic findings were not found. Instead, the bis -deficient mice developed by us revealed significant hypoglycemia, fatty livers, loss of peripheral fat reserves and increased glucocorticoid levels, all of which are typical adaptive response to malnutrition [22, 23]. Thus, a serious nutritional problem might be more closely connected with the early lethality of bis -/- mice, but the precise molecular basis for this are not understood.…”