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Prenatal overexpression of platelet-derived growth factor receptor A results in central nervous system
Herminio Joey Cardona1, Agila Somasundaram1, Donna M Crabtree2,3
1Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital, Chicago, Illinois, USA.
Insights
Embryonic overexpression of human Platelet-Derived Growth Factor Receptor Alpha (hPDGFRA) in progenitor cells disrupts oligodendrocyte development, leading to severe central nervous system hypomyelination in mice.
Area of Science:
- Neuroscience
- Developmental Biology
- Oncology
Background:
- Platelet-derived growth factor (PDGF) signaling is crucial for oligodendrocyte progenitor cell (OPC) growth and maintenance in the central nervous system (CNS).
- PDGFRA signaling normally decreases before OPCs differentiate into myelinating oligodendrocytes.
- PDGFRA amplification/mutation is common in gliomas, particularly diffuse midline glioma (DMG), suggesting OPCs as a cell-of-origin.
Purpose of the Study:
- To investigate the in vivo cellular and molecular consequences of unregulated PDGFRA expression in OPCs.
- To model the effects of PDGFRA dysregulation relevant to glioma development.
Main Methods:
- Created a conditional knock-in (KI) mouse model overexpressing wild-type human PDGFRA (hPDGFRA) in prenatal Olig2-expressing progenitors.
- Examined in vivo cellular and molecular outcomes.
- Performed RNA-sequencing analysis to assess gene expression changes related to myelination.
Main Results:
- KI mice showed stunted growth, ataxia, and severe CNS hypomyelination.
- Combined PDGFRA overexpression with p53 loss prevented tumor formation but retained hypomyelination.
- RNA-sequencing revealed decreased myelination gene signatures, indicating impaired oligodendroglial development.
- Overexpression in GFAP-expressing progenitors also led to myelination defects.
Conclusions:
- Embryonic hPDGFRA overexpression in Olig2- or GFAP-progenitors is detrimental to OPC development.
- This dysregulation results in significant CNS hypomyelination.
- The findings provide insights into the cellular and molecular impact of PDGFRA dysregulation in the context of CNS development and glioma origins.
Background:
Platelet-derived growth factor (PDGF) signaling, through the ligand PDGF-A and its receptor PDGFRA, is important for the growth and maintenance of oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS). PDGFRA signaling is downregulated prior to OPC differentiation into mature myelinating oligodendrocytes. By contrast, PDGFRA is often genetically amplified or mutated in many types of gliomas, including diffuse midline glioma (DMG) where OPCs are considered the most likely cell-of-origin. The cellular and molecular changes that occur in OPCs in response to unregulated PDGFRA expression, however, are not known.
Methods:
Here, we created a conditional knock-in (KI) mouse that overexpresses wild type (WT) human PDGFRA (hPDGFRA) in prenatal Olig2-expressing progenitors, and examined in vivo cellular and molecular consequences.
Results:
The KI mice exhibited stunted growth, ataxia, and a severe loss of myelination in the brain and spinal cord. When combined with the loss of p53, a tumor suppressor gene whose activity is decreased in DMG, the KI mice failed to develop tumors but still exhibited hypomyelination. RNA-sequencing analysis revealed decreased myelination gene signatures, indicating a defect in oligodendroglial development. Mice overexpressing PDGFRA in prenatal GFAP-expressing progenitors, which give rise to a broader lineage of cells than Olig2-progenitors, also developed myelination defects.
Conclusion:
Our results suggest that embryonic overexpression of hPDGFRA in Olig2- or GFAP-progenitors is deleterious to OPC development and leads to CNS hypomyelination.
