Neuronal stress promotes Cre recombinase transfer from oligodendroglia to neurons

The study of oligodendrocyte precursor cells (OPCs) in both physiological and pathological contexts is challenging due to their capacity for self-renewal. This research aimed to examine the effects of OPC depletion on neurons. Tamoxifen-inducible Sox10/iCreER^T2; netrin-1^flox/flox (NTN-1 cKO) mice were used to inactivate NTN-1 in Sox10⁺ oligodendroglia at varying tamoxifen doses. The impact of Necrostatin-1s (Nec-1s) and cytarabine on neuronal degeneration was evaluated, along with a comparison of the effects of tamoxifen dissolved in different plant oils on lineage tracing in Sox10/iCreER^T2; tdTomato mice, as well as on neuronal degeneration in NTN-1 cKO mice. Our findings showed that administering 3 mg of tamoxifen per NTN-1 cKO mouse triggered necroptosis and apoptosis in Sox10⁺ cells. Notably, a higher dose of 6 mg of tamoxifen resulted in the degeneration of cortical neurons, which was accompanied by astrogliosis, amyloidosis, and a reduction in microglia. Immunostaining and RNAscope analysis indicated that it was Cre recombinase, rather than Cre mRNA, that was transferred to neurons. Nec-1s and cytarabine successfully prevented cortical neuron degeneration, though through distinct mechanisms. Furthermore, administering tamoxifen dissolved in vitamin E-rich wheat germ oil reduced Cre transfer in both Sox10/iCreER^T2; tdTomato mice and NTN-1 cKO mice, significantly preventing cortical neurons from being labeled with tdTomato and protecting them from degeneration. These results suggest that, under pathological conditions, Cre recombinase can transfer from oligodendroglia to neurons, a process triggered by neuronal stress. This highlights the need for careful consideration in using Cre-loxP lineage tracing and gene-editing methods involving oligodendrocyte lineage cells and neurons.