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bioRxiv · 10.1101/2022.12.31.522394

Autophagy collaborates with apoptosis pathways to control myelination specificity and function

Zhang, T.·Bae, H.-G.·Bhambri, A.·Zhang, Y.·Barbosa, D.·Xue, J.·Wazir, S.·Mulinyawe, S. B.·Kim, J. H.·Sun, L. O.
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Abstract

Oligodendrocytes are the sole myelin producing cells in the central nervous system. Oligodendrocyte numbers are tightly controlled across diverse brain regions to match local axon type and number, but the underlying mechanisms and functional significance remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under canonical settings, elicits premyelinating oligodendrocyte apoptosis during development and regulates critical aspects of nerve pulse propagation. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy acts in the TFEB-Bax/Bak pathway and elevates PUMA mRNA levels to trigger premyelinating oligodendrocyte apoptosis cell-autonomously. Autophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath numbers and fine-tune nerve pulse propagation. Our results provide in vivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrocyte number. HIGHLIGHTSO_LIAutophagy flux increases in the premyelinating and myelinating oligodendrocytes C_LIO_LIAutophagy promotes premyelinating oligodendrocyte (pre-OL) apoptosis to control myelination location and timing C_LIO_LIAutophagy acts in the TFEB-PUMA-Bax/Bak pathway and elevates PUMA mRNA levels to determine pre-OL fate C_LIO_LIAutophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath thickness and finetune nerve pulse propagation C_LI

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Zhang, T., Bae, H.-G., Bhambri, A., Zhang, Y., Barbosa, D., Xue, J., Wazir, S., Mulinyawe, S. B., Kim, J. H., Sun, L. O.. 2023-01-02. Autophagy collaborates with apoptosis pathways to control myelination specificity and function. https://doi.org/10.1101/2022.12.31.522394

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