NF-?B activity during pancreas development regulates adult ?-cell mass by modulating neonatal ?-cell proliferation and apoptosis.

ABSTRACT: NF-?B is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in ?-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-?B in vivo, we have generated two transgenic mouse models, the ToI? and NOD/ToI? mice, in which NF-?B activation is specifically and conditionally inhibited in ?-cells. In this study, we present a novel function of the canonical NF-?B pathway during murine islet ?-cell development. Interestingly, inhibiting the NF-?B pathway in ?-cells during embryogenesis, but not after birth, in both ToI? and NOD/ToI? mice, increased ?-cell turnover, ultimately resulting in a reduced ?-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-?B p65-subunit was found in neonatal ?-cells, significant activation was not detected in ?-cells of either adult NOD/ToI? mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToI? mice, inhibiting NF-?B post-weaning had no effect on the development of diabetes or ?-cell dysfunction. In conclusion, our data point to NF-?B as an important component of the physiological regulatory circuit that controls the balance of ?-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating ?-cell mass and the development of diabetes in the mouse model of T1D.

SUBMITTER: Sever D 

PROVIDER: S-EPMC7790827 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature