Mus musculus musculus Raw sequence reads

Oligodendrocytes are the sole myelin-producing cells in the central nervous system. Oligodendrocyte number is tightly controlled across diverse brain regions to match local axon type and number, yet the underlying mechanisms remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under physiological conditions, elicits premyelinating oligodendrocyte apoptosis during development. Autophagy flux is increased in the premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy functions cell-autonomously in the premyelinating oligodendrocyte to trigger cell apoptosis, and it genetically interacts with the TFEB pathway to control oligodendrocyte number across diverse brain regions. Our results provide in vivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrogenesis.