Overexpression ofH3K36methyltransferaseNSDin glial cells affects brain development inDrosophila

NSD1 is a histone methyltransferase that methylates the lysine 36 at histone H3.NSDduplication is associated with short stature, microcephaly, intellectual disability, and behavioral defects in humans. Ectopic overexpression ofNSD, anNSD1homolog inDrosophila, was shown to induce developmental abnormalities via apoptosis. In this study, to investigate the effects ofNSDoverexpression onDrosophilabrain development, we first examined the typicalNSDexpression pattern in larval brains and found that endogenousNSDpromoter activity was detected only in subsets of glial cells. Pan-glial, but not pan-neuronal,NSDoverexpression induced apoptosis in larval brain cells. However, pan-glialNSDoverexpression also induced caspase-3 cleavage in neuronal cells. Among the various glial cell types,NSDoverexpression in only astrocytic glia induced apoptosis and abnormal learning defects in the larval stage. Furthermore,NSDoverexpression downregulated the expression of various astrocyte-specific genes, includingdraper(drpr), possibly owing to an indirect effect ofNSDoverexpression-induced astrocytic apoptosis. Sincedrprplays a role in axon pruning during mushroom body (MB) formation inDrosophilaastrocytes, we examined the effect of astrocyticNSDoverexpression on this process and found that it disrupted the clearance of gamma-neurons in the MB, subsequently inducing arrhythmic locomotor activity of the fly. Thus, these results suggest that aberrantNSDoverexpression may cause neurodevelopmental disorders by interfering with crucial functions of astrocytes in the brain, underlining the importance of the tightly controlled astrocyticNSDexpression for proper neurodevelopment.