The Key Role of p75NTR in Oligodendrocyte Genesis and Brain Myelination

Oligodendrocytes play a central role in the formation of myelin which surrounds and insulates nerve fibers in the central nervous system (CNS). The development of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes is a complex and finely regulated process that is critical for healthy brain function. It occurs both during embryonic growth and continues into adulthood which highlights the dynamic nature of myelination and its importance in brain plasticity and repair. Any disruptions in the lifecycle from progenitor cell proliferation to myelination can lead to serious neurological conditions such as multiple sclerosis and, neonatal brain injuries.  Better understanding of oligodendrocyte progenitor cells and their ability to generate new oligodendrocytes is important in developing therapies aimed at CNS repair, such as in spinal cord injuries or demyelinating diseases. In a new study published in Glia Journal and conducted by Subhashini Joshi, Michelle Frondelli, Dr. Juan Zanin, Professor Steven Levison, and Professor Wilma Friedman from Rutgers University, the authors investigated the role of the p75 neurotrophin receptor (p75NTR) in OPC development from the postnatal rat subventricular zone (SVZ). The SVZ is a vital neural stem cell niche in the brain that undergoes dynamic changes throughout development. In the postnatal period, it serves as a critical source for the generation of oligodendrocytes. Their study encompassed a series of in-depth experiments, each contributing to a comprehensive understanding of how p75NTR regulates OPC development, differentiation, and myelination in the postnatal brain.

The researchers began by analyzing the expression pattern of p75NTR in the SVZ of postnatal rats. They demonstrated that p75NTR was highly expressed in the OPCs residing in the male and female rat SVZ during the postnatal period. This finding was significant as it suggested a developmental role for p75NTR beyond its known function in apoptotic signaling following brain injury. The team employed both p75NTR knockout (KO) rats and wild-type (WT) counterparts to investigate the function of p75NTR and assessed the impact of p75NTR deficiency on OPC proliferation, differentiation, and subsequent myelination. They used SVZ derived cells and performed neurosphere assays to evaluate the role of p75NTR in progenitor cell proliferation. They found that p75NTR-positive (p75NTR+) cells formed larger and more numerous neurospheres compared to p75NTR-negative (p75NTR-) cells and cells from p75NTR KO rats. This indicated that p75NTR supports the proliferation of OPCs in the SVZ. To understand how p75NTR influences OPC differentiation, the researchers cultured SVZ-derived cells under conditions promoting differentiation. They observed that the absence of p75NTR led to premature differentiation and maturation of OPCs into oligodendrocytes, both in vitro and in vivo. This was evidenced by the increased expression of oligodendrocyte markers such as Olig2 and MBP (Myelin Basic Protein) in p75NTR- and p75NTR KO cells, indicating aberrant early myelin formation.

Additionally, the team assessed the migratory behavior of OPCs by using transwell migration assays, and found that p75NTR KO OPCs exhibited increased migration compared to WT OPCs, which suggests that p75NTR regulates as well the migration of OPCs within the brain. Moreover, to corroborate the in vitro findings, the researchers conducted in vivo studies to examine myelination in the brains of p75NTR KO and WT rats. They discovered abnormal early myelin formation in p75NTR KO rats, as indicated by increased and disorganized MBP expression in the corpus callosum, a key white matter tract. This abnormal myelination pattern highlighted the critical role of p75NTR in regulating the timing and progression of myelin development.

One key finding is that p75NTR expression is not uniform across species or even within different developmental stages of the same species, indicating a complex regulatory mechanism at play. In rats, p75NTR is prominently expressed in the SVZ during the postnatal period, coinciding with peak oligodendrogenesis. This expression pattern contrasts with observations in adult animals and other species, suggesting species-specific and developmental stage-specific roles for p75NTR. The study also explored the signaling pathways and molecular mechanisms through which p75NTR exerts its effects on OPCs. While p75NTR is known to interact with various neurotrophins and their receptors, its specific signaling pathways in OPC development and myelination remain to be fully elucidated. The authors suggest that p75NTR may act as a molecular “rheostat” that finely tunes the balance between OPC proliferation and differentiation, ensuring the timely production and maturation of oligodendrocytes necessary for myelin formation.

In conclusion, the study by Professor Friedman and colleagues advanced our understanding of the complex molecular landscape for OPC development and myelination in the postnatal brain. They demonstrated that the p75NTR, traditionally associated with apoptotic signaling post-injury in the brain, is highly expressed in proliferating OPCs within the SVZ during development and proposed a novel, non-apoptotic role for p75NTR in the brain’s development, particularly in regulating oligodendrocyte production and maturation to ensure proper brain function. Further research in this direction could lead to novel therapeutic strategies for demyelinating diseases and other neurological disorders associated with myelination defects.