Neural tube defects induce abnormal astrocyte development by activation and epigenetic permissiveness of STAT3

The open neural tube defect, myelomeningocele (MMC), is a debilitating congenital defect of the central nervous system, characterized by impaired spinal cord development. The pathological development of MMC spinal cord involves enhanced astrogenesis. However, the mechanisms underlying the abnormal generation of astrocytes in MMC spinal cord are poorly understood. Using a fetal rat model of this defect, we discovered that neural progenitor cells (NPCs) in the developing spinal cord undergo the accelerated acquisition of astrocytic competency and the abnormal induction of GFAP expression, resulting in the enhanced generation of astrocytes. We identified that the activation of signal transducer and activator of transcription 3 (STAT3) in NPCs, accompanied by the early epigenetic modifications at the consensus STAT3 binding site within the Gfap promoter, induces this pathological process. Furthermore, we demonstrated that the amniotic fluid exposure is the stimulator of STAT3 activation in MMC spinal cord NPCs, promoting GFAP expression and differentiation of NPCs into astrocytes. To validate this mechanism, we showed that elimination of Stat3 expression from NPCs using CRISPR/Cas9 inhibited GFAP expression and the emergence of astrocytes. Thus, our study provides a novel mechanism that drives abnormal astrogenesis in the developing MMC spinal cord.