Prenatal overexpression of platelet‐derived growth factor receptor A results in central nervous system hypomyelination

Abstract

Abstract 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.

Keywords

• brain tumors
• diffuse midline glioma
• hypomyelination
• myelination
• oligodendrocyte precursor cells
• PDGF