Biology subjects

Sun, L. O.

Publications and source records attributed to Sun, L. O..

4 recordsLinked to original sources

bioRxiv2026

Oligodendrocyte ER-phagy Restricts Excessive Myelination by Degrading Sphingolipid Synthases

Myelination is critical for nervous system function. Numerous signaling pathways have been identified that promote myelin sheath growth, disruption of which can lead to hypomyelination, characterized by a reduction in myelin sheath thickness. However, the negative regulators of myelin sheath expansion remain poorly defined. Here, we identify a cellular brake on central nervous system myelination that restricts myelin sheath thickness during brain development. This brake is mediated by a selective form of autophagy, known as endoplasmic reticulum (ER)-phagy, which degrades the ER and its resident sphingolipid synthases. ER-phagy is highly active in oligodendrocytes during myelin membrane expansion, and its impairment leads to ER accumulation, elevated sphingolipid production, and excessive myelin thickening. Genetic reduction of de novo sphingolipid biosynthesis in the ER rescues the hypermyelination phenotype caused by ER-phagy disruption. In summary, our findings establish ER-phagy as a key regulator of sphingolipid metabolism and reveal a mechanistic link between ER homeostasis and myelin production by oligodendrocytes, providing insight into mechanisms underlying pathological hypermyelination.

neuroscience↗

bioRxiv2023

Autophagy collaborates with apoptosis pathways to control myelination specificity and function

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

neuroscience↗

bioRxiv2022

Oligodendrocyte-lineage cell exocytosis and L-type prostaglandin D synthase 1 promote oligodendrocyte development and myelination

In the developing central nervous system, oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes, which form myelin around axons. Oligodendrocytes and myelin are essential for the function of the central nervous system, as evidenced by the severe neurological symptoms that arise in demyelinating diseases such as multiple sclerosis and leukodystrophy. Although many cell-intrinsic mechanisms that regulate oligodendrocyte development and myelination have been reported, it remains unclear whether interactions among oligodendrocyte-lineage cells (OPCs and oligodendrocytes) affect oligodendrocyte development and myelination. Here, we show that blocking vesicle-associated membrane protein (VAMP) 1/2/3-dependent exocytosis from oligodendrocyte-lineage cells impairs oligodendrocyte development, myelination, and motor behavior in mice. Adding oligodendrocyte-lineage cell-secreted molecules to secretion-deficient OPC cultures partially restores the morphological maturation of oligodendrocytes. Moreover, we identified L-type prostaglandin D synthase as an oligodendrocyte-lineage cell-secreted protein that promotes oligodendrocyte development and myelination in vivo. These findings reveal a novel autocrine/paracrine loop model for the regulation of oligodendrocyte and myelin development.

neuroscience↗

bioRxiv2018

Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing

Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown if these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, postnatal, and adult mouse brains. We found that the majority of adult microglia with homeostatic signatures are remarkably similar in transcriptomes, regardless of brain region. By contrast, postnatal microglia represent a more heterogeneous population. We discovered that postnatal white matter-associated microglia (WAM) are strikingly different from microglia in other regions and express genes enriched in degenerative disease-associated microglia. These postnatal WAM have distinct amoeboid morphology, are metabolically active, and phagocytose newly formed oligodendrocytes. This scRNA-seq atlas will be a valuable resource for dissecting innate immune functions in health and disease.\n\nHighlightsO_LIMyeloid scRNA-seq atlas across brain regions and developmental stages\nC_LIO_LILimited transcriptomic heterogeneity of homeostatic microglia in the adult brain\nC_LIO_LIPhase-specific gene sets of proliferating microglia along cell cycle pseudotime\nC_LIO_LIPhagocytic postnatal white matter-associated microglia sharing DAM gene signatures\nC_LI

neuroscience↗