Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner

Luis Zurkirchen,Nicola Zamboni,Sandra Varum,Raphaël Bossart,Annika Klug,Konrad Basler,Martina Zemke,Lukas Sommer,Zeynep Kalender Atak,Claudio Cantù,Sonja Giger,Jessica Häusel

doi:10.1038/s41467-019-09823-5

Luis Zurkirchen, Nicola Zamboni + Show 10 more

Open Access

https://doi.org/10.1038/s41467-019-09823-5

Copy DOI

Abstract

The transcription factor Yin Yang 1 (YY1) plays an important role in human disease. It is often overexpressed in cancers and mutations can lead to a congenital haploinsufficiency syndrome characterized by craniofacial dysmorphisms and neurological dysfunctions, consistent with a role in brain development. Here, we show that Yy1 controls murine cerebral cortex development in a stage-dependent manner. By regulating a wide range of metabolic pathways and protein translation, Yy1 maintains proliferation and survival of neural progenitor cells (NPCs) at early stages of brain development. Despite its constitutive expression, however, the dependence on Yy1 declines over the course of corticogenesis. This is associated with decreasing importance of processes controlled by Yy1 during development, as reflected by diminished protein synthesis rates at later developmental stages. Thus, our study unravels a novel role for Yy1 as a stage-dependent regulator of brain development and shows that biosynthetic demands of NPCs dynamically change throughout development.

Highlights

The transcription factor Yin Yang 1 (YY1) plays an important role in human disease
Quantitative real-time polymerase chain reaction (QRT-PCR) analysis and immunostaining demonstrated that Yy1 mRNA and protein were prominently expressed throughout cortical development, with a slight decrease in overall expression levels at late developmental stages (Supplementary Fig. 1a–c)
Yy1 is crucial during early cortical development to sustain neural progenitor cells (NPCs) proliferation and survival, in contrast to developmental stages after the first waves of neurogenesis when the activity of Yy1 seems to be dispensable for cortex development

Summary

Introduction

The transcription factor Yin Yang 1 (YY1) plays an important role in human disease It is often overexpressed in cancers and mutations can lead to a congenital haploinsufficiency syndrome characterized by craniofacial dysmorphisms and neurological dysfunctions, consistent with a role in brain development. The dependence on Yy1 declines over the course of corticogenesis This is associated with decreasing importance of processes controlled by Yy1 during development, as reflected by diminished protein synthesis rates at later developmental stages. Yy1 has been shown to be required for proper differentiation of the oligodendrocytic lineage at postnatal stages in vivo[15] It is still unclear how cell type-specific functions of such an ubiquitous factor are achieved, the central nervous system and craniofacial structures appear to be especially dependent on the activity of YY1 as evidenced by the phenotype of YY1 loss-of-function in human patients[1]. At later stages of cortex development, Yy1 inactivation did not affect metabolic processes anymore and the rate of protein synthesis was generally reduced in later stage NPCs, revealing stage-dependent demands for metabolism and protein translation in cortical development

Methods

Results

Conclusion