ASCL1 promotes nuclear shrinkage in transdifferentiation by suppressing NUP37

Abstract

Despite the central role of the nucleus in the cell, it remains unclear what determines nuclear size. Previous studies suggest a correlation between nuclear and cell size. However, many neurons have massive axon arbors, while maintaining a typical nuclear size. Here, we show a marked reduction of nuclear, but not cell, size during the direct conversion of human fibroblasts to induced neurons by ASCL1, miR124-9-9^∗, and p53 short hairpin RNA (shRNA) (AMp). Similar nuclear shrinkage was observed in the maturation of induced pluripotent stem cell-derived human cortical neurons. ASCL1 suppressed the transcription of the nucleoporin NUP37 by direct binding to its promoter. NUP37 knockdown enhanced AMp-mediated transdifferentiation and nuclear shrinkage, while NUP37 overexpression achieved the opposite. It appears that ASCL1 promotes nuclear shrinkage by suppressing NUP37 and reducing the nuclear pore complex (NPC), which gates nuclear transport. The study suggests a critical role of NPC in controlling nuclear size to match cell state.

Keywords: ASCL1; Direct neuronal reprogramming; NUP37; induced neurons; nuclear pore complex; nuclear shrinkage; nucleoporin; transdifferentiation.