Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis

Nervous system function depends on proper myelination for insulation and critical trophic support for axons. Myelination is tightly regulated spatially and temporally, but how it is controlled molecularly remains largely unknown. Here, we identified key molecular mechanisms governing the regional and temporal specificity of CNS myelination. We show that transcription factor EB (TFEB) is highly expressed by differentiating oligodendrocytes and that its loss causes precocious and ectopic myelination in many parts of the murine brain. TFEB functions cell-autonomously through PUMA induction and Bax-Bak activation to promote programmed cell death of a subset of premyelinating oligodendrocytes, allowing selective elimination of oligodendrocytes in normally unmyelinated brain regions. This pathway is conserved across diverse brain areas and is critical for myelination timing. Our findings define an oligodendrocyte-intrinsic mechanism underlying the spatiotemporal specificity of CNS myelination, shedding light on how myelinating glia sculpt the nervous system during development. [Display omitted] •Transcription factor EB (TFEB) is highly expressed by premyelinating oligodendrocytes•TFEB functions cell-autonomously to eliminate OLs in unmyelinated brain regions•TFEB activates the PUMA-Bax-Bak pathway to control myelination location and timing•TFEB induces ER stress gene expression in OLs and sets a brake on CNS myelination Programmed cell death actively eliminates oligodendrocytes in non-myelinated brain regions to ensure region-specific myelination. Transcription factor EB activates the PUMA-Bax-Bak pathway to promote programmed cell death of subsets of premyelinating oligodendrocytes, allowing temporal and regional specificity of CNS myelination.