Abstract: Yy1 is integral to several key biological processes, including cell cycle regulation, proliferation, and survival, particularly in stem cell contexts. Patients with Gabriele-De Vries syndrome, caused by dominant mutations in Yy1, exhibit significant developmental defects in the central nervous system (CNS). Despite its importance, the role of Yy1 in mammalian CNS development, especially in cerebellar neural stem cell populations, is not fully understood. To investigate Yy1's role in the development of cerebellar neural stem cell populations, we employed a tissue-specific Cre-LoxP system using two different Cre-expressing mouse lines, Pax7-Cre and En1-Cre. This approach allowed for the selective inactivation of Yy1 in stem cell renewal and specification within the primary neural germinal zones and the developing MHB region, where the isthmus organizer, located at the mid-hindbrain (MHB) boundary, acts as a critical signaling center influencing the early patterning of both the midbrain and cerebellum—areas rich in neural progenitor cells. Our findings reveal distinct morphological phenotypes in the Pax7-Cre and En1-Cre-driven Yy1 knockout mutants. Both YY1 mutant models resulted in severe cerebellar hypoplasia with less foliation. Furthermore, the Wnt/β-catenin signaling pathway may be a key molecular mechanism underlying developmental defects in En1-Cre Yy1 mutant mes/r1 neuroepithelial stem cells. In summary, our research highlights the crucial functions of YY1 in neural stem cell maintenance, renewal, and specification during cerebellar development, as well as in sustaining mouse mes/r1 neuroepithelial stem cell populations. It underscores essential role of Yy1 in the early development of the mid-hindbrain neural tube and provides valuable insights into the roles of YY1 in various neural stem cell populations.
