Yin Yang 1 is critical for mid-hindbrain neuroepithelium development and involved in cerebellar agenesis

The highly conserved and ubiquitously expressed transcription factorYin Yang 1(Yy1), was named after its dual functions of both activating and repressing gene transcription.Yy1plays complex roles in various fundamental biological processes such as the cell cycle progression, cell proliferation, survival, and differentiation. Patients with dominantYy1mutations suffer from central nervous system (CNS) developmental defects. However, the role ofYy1in mammalian CNS development remains to be fully elucidated. The isthmus organizer locates to the mid-hindbrain (MHB) boundary region and serves as the critical signaling center during midbrain and cerebellar early patterning. To study the function ofYy1in mesencephalon/ rhombomere 1 (mes/r1) neuroepithelium development, we utilized the tissue-specificCre-LoxPsystem and generated a conditional knockout mouse line to inactivateYy1in the MHB region. Mice withYy1deletion in the mes/r1 region displayed cerebellar agenesis and dorsal midbrain hypoplasia. TheYy1deleted neuroepithelial cells underwent cell cycle arrest and apoptosis, with the concurrent changes of cell cycle regulatory genes expression, as well as activation of the p53 pathway. Moreover, we found thatYy1is involved in the transcriptional activation ofWnt1in neural stem cells. Thus, our work demonstrates the involvement ofYy1in cerebellar agenesis and the critical function ofYy1in mouse early MHB neuroepithelium maintenance and development.