@article{Kamen21012025,
author = {Kamen, Yasmine and Chapman, Timothy W. and Piedra, Enrique T. and Ciolkowski, Matthew E. and Hill, Robert A.}, 
title = {Transient upregulation of procaspase-3 during oligodendrocyte fate decisions},
year = {2025}, 
doi = {10.1523/JNEUROSCI.2066-24.2025}, 
abstract ={Oligodendrocytes are generated throughout life and in neurodegenerative conditions from brain resident oligodendrocyte precursor cells (OPCs). The transition from OPC to oligodendrocyte involves a complex cascade of molecular and morphological states that position the cell to make a fate decision to integrate as a myelinating oligodendrocyte or die through apoptosis. Oligodendrocyte maturation impacts the cell death mechanisms that occur in degenerative conditions, but it is unclear if and how the cell death machinery changes as OPCs transition into oligodendrocytes. Here, we discovered that differentiating oligodendrocytes transiently upregulate the zymogen procaspase-3 in both female and male mice, equipping these cells to make a survival decision during differentiation. Pharmacological inhibition of caspase-3 decreases oligodendrocyte density, indicating that procaspase-3 upregulation is linked to successful oligodendrocyte generation. Moreover, using procaspase-3 as a marker, we show that oligodendrocyte differentiation continues in the aging cortex and white matter. Taken together, our data establish procaspase-3 as a differentiating oligodendrocyte marker and provide insight into the underlying mechanisms occurring during the decision to integrate or die.Significance statement Myelin dysfunction and oligodendrocyte death occur in several neurological disorders and with aging. While new oligodendrocytes can be generated from oligodendrocyte precursor cells throughout life and in neurodegenerative conditions, this process is inefficient with many differentiating oligodendrocytes failing to integrate and dying. Investigating the cellular checkpoints that regulate these fate decisions is complicated by a paucity of molecular markers precisely delineating differentiation stages. Here, we identify that oligodendrocytes transiently upregulate the zymogen procaspase-3 during differentiation, establishing procaspase-3 as a differentiating oligodendrocyte marker. Importantly, procaspase-3 upregulation equips differentiating oligodendrocytes for a fate decision between death or integration and promotes oligodendrocyte differentiation. Thus, our data uncover new insights into mechanisms guiding oligodendrocyte fate decisions.}, 
URL = {http://www.jneurosci.org/content/early/2025/01/17/JNEUROSCI.2066-24.2025.abstract}, 
eprint = {http://www.jneurosci.org/content/early/2025/01/17/JNEUROSCI.2066-24.2025.full.pdf+html}, 
journal = {The Journal of Neuroscience} 
}