Generation and characterization of the TRE-TNFR2 transgenic mouse for cell-specific and timed (over)expression of...

Tumor necrosis factor receptor 2 (TNFR2), the signaling partner of the transmembrane form of tumor necrosis factor (tmTNF), is implicated in cell survival and tissue healing processes. Despite recent advances, our knowledge of the precise cellular mechanisms engaged by TNFR2 and, most importantly, its downstream targets is still limited. To address this gap, we generated tetracycline responsive element (TRE)-TNFR2 transgenic mice that, once crossed with tetracycline-controlled trans-activator (tTA) or reverse tetracycline-controlled trans-activator (rtTA) transgenics, allow for timed (over)expression of TNFR2 in a cell of interest based on administration (Tet-On) or withdrawal (Tet-Off) of doxycycline (DOX). TRE-TNFR2 mice were characterized upon crossing with various tTA and rtTA transgenics, demonstrating efficient and specific expression in neurons, oligodendrocyte lineage cells, and astrocytes. Overexpressed TNFR2 was found to be functional, as TNFR2-dependent activation of PI3K/AKT signaling was observed both in vitro in primary mature oligodendrocyte cultures obtained from PLP^tTA:TNFR2^TRE mice overexpressing TNFR2, and in vivo in spinal cord oligodendrocytes of PLP^tTA:TNFR2^TRE mice induced with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Furthermore, PLP^tTA:TNFR2^TRE mice showed delayed onset and peak EAE compared to control mice, indicating a beneficial role for TNFR2 expressed by myelinating oligodendrocytes in CNS demyelinating disease. Collectively, this evidence supports the validity of the TRE-TNFR2 mouse model as a tool to investigate molecules and cascades engaged by TNFR2 in vivo that may be targeted for therapeutic purposes.