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

Abstract

SUMMARY 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 central nervous system (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 for 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.

Low‐intensity transcranial magnetic stimulation promotes the survival and maturation of newborn oligodendrocytes in the adult mouse brain

“…iTBS could act directly on premyelinating oligodendrocytes to influence their survival, as the transcription factor EB can turn on expression of Bbc3 (Bcl binding component 3) and activate Bax‐Bak signaling to trigger apoptotic cell death (Sun et al, ). However, it is also possible that this effect is secondary to an increase in neuronal activity (Kougioumtzidou et al, ; Palser, Norman, Saffell, & Reynolds, ; Trapp et al, ; Xiao et al, ).…”

Glutamate versus GABA in neuron–oligodendroglia communication

“…Interestingly, the activation of GABA A Rs in Cajal Retzius neurons, for which GABA is also depolarizing, causes their programmed cell death through dynamic changes of intracellular Cl − concentrations involving the Cl − transporter NKCC1 and p75NTR signaling (Blanquie, Liebmann, Hübner, Luhmann, & Sinning, ; Kolbaev, Luhmann, & Kilb, ). Programmed cell death is also an important mechanism of oligodendroglia to ensure OL lineage cell balance and region‐specific myelination (Kessaris et al, ; Sun et al, ). It would thus be interesting to test if a mechanism similar to that described for Cajal Retzius neurons, whether synaptic or extrasynaptic, promotes either the death or the survival of oligodendroglia.…”

Oligodendrocytes in intracerebral hemorrhage

“…Markers for pre‐OLs are relatively less well characterized. A recent study reported that TFEB (transcription factor EB) is highly enriched in pre‐OLs and can be used as a pre‐OL marker . In addition, O4 has been also suggested as a pre‐OL marker, although there is also evidence showing that it is also expressed in mature‐OLs .…”

“…A recent study reported that TFEB (transcription factor EB) is highly enriched in pre-OLs and can be used as a pre-OL marker. 48 In addition, O4 has been also suggested as a pre-OL marker, 40,44,49 although there is also evidence showing that it is also expressed in mature-OLs. 50,51 Mature-OLs form myelin sheaths and express a group of unique proteins, including MYRF (myelin regulatory factor), 52 MBP (myelin basic protein), 38,44,53 MOG (myelin oligodendrocyte glycoprotein), [54][55][56] PLP (proteolipid protein), 44,53,57 and MAG (myelin-associated glycoprotein).…”