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

Abstract

The highly conserved and ubiquitously expressed transcription factor Yin Yang 1 ( Yy1 ), was named after its dual functions of both activating and repressing gene transcription. Yy1 plays complex roles in various fundamental biological processes such as the cell cycle progression, cell proliferation, survival, and differentiation. Patients with dominant Yy1 mutations suffer from central nervous system (CNS) developmental defects. However, the role of Yy1 in 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 of Yy1 in mesencephalon/ rhombomere 1 (mes/r1) neuroepithelium development, we utilized the tissue-specific Cre-LoxP system and generated a conditional knockout mouse line to inactivate Yy1 in the MHB region. Mice with Yy1 deletion in the mes/r1 region displayed cerebellar agenesis and dorsal midbrain hypoplasia. The Yy1 deleted 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 that Yy1 is involved in the transcriptional activation of Wnt1 in neural stem cells. Thus, our work demonstrates the involvement of Yy1 in cerebellar agenesis and the critical function of Yy1 in mouse early MHB neuroepithelium maintenance and development.

Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology

“…Differences in cerebellar size between mutant and control embryos were already apparent by E13.5 ( Figure 2D). Although the trilaminar structure of the cerebellum appeared normal in En1-Cre; Hbs1l cKO mice at postnatal day P21, cerebellar foliation was delayed in P0 mutant mice, and secondary fissures failed to form compared to control mice ( Figure 2D) and consistent with previous studies no cerebellar abnormalities were observed in En1-Cre mice (Dong and Kwan, 2020;Guo et al, 2010;Li et al, 2002;Sgaier et al, 2007;Tripathi et al, 2008).…”

The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1

“…Several studies show that YY1 plays a role in neurodevelopmental disorders (Donohoe et al, 1999;Varum et al, 2019;Zurkirchen et al, 2019), but the mechanisms behind this are still incompletely understood. In mouse embryos, YY1 has proven essential for neurodevelopment (Varum et al, 2019;Zurkirchen et al, 2019;Dong and Kwan, 2020). In murine models, Yy1 conditional knock-out (cKO) induced at an early stage of cortical development, caused an increased apoptosis rate and cell cycle arrest in neuroepithelium and NPCs (Zurkirchen et al, 2019;Dong and Kwan, 2020).…”

“…In mouse embryos, YY1 has proven essential for neurodevelopment (Varum et al, 2019;Zurkirchen et al, 2019;Dong and Kwan, 2020). In murine models, Yy1 conditional knock-out (cKO) induced at an early stage of cortical development, caused an increased apoptosis rate and cell cycle arrest in neuroepithelium and NPCs (Zurkirchen et al, 2019;Dong and Kwan, 2020). This effect on NPCs however decreased markedly when cKO was induced at later stages (Zurkirchen et al, 2019).…”

“…The importance of YY1 in early development is also attributed to apoptosis inhibition (Sui et al, 2004;Chen et al, 2018;Zurkirchen et al, 2019;Dong and Kwan, 2020). In mice, cKO of Yy1 at an early embryonic stage caused an accumulation of p53 protein and increased apoptosis (Zurkirchen et al, 2019;Dong and Kwan, 2020). This effect could be partially reversed in Yy1/Trp53 double cKO mice, indicating that YY1 is important in the downregulation of p53, an important apoptosis regulator, to facilitate NPC survival (Zurkirchen et al, 2019).…”

Roles Played by YY1 in Embryonic, Adult and Cancer Stem Cells

“…Additionally, a marked reduction in neural crest derivatives located in the enteric nervous system, dorsal root ganglia, and skin was observed in this model [ 50 ]. Dong and colleagues demonstrated that Cre-mediated deletion of the YY1 gene in the mid-hindbrain region induced hypoplasia and cerebellar agenesis by inhibiting cell cycle progression and inducing apoptotic death in neuroepithelial stem cells in a p53-dependent manner [ 51 ]. Another study demonstrated that knockout of the YY1 gene during cortex development decreased the forebrain size due to reduced proliferation and increased apoptotic death in cortical progenitor cells [ 52 ].…”