Yin Yang 1 sets up the stage for cerebellar astrocyte maturation

Abstract

Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain mature astrocytes in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.

Astrocytic Yin Yang 1 is critical for murine brain development and protection against apoptosis, oxidative stress, and inflammation

“…Studies have also shown that YY1 deletion in the mid‐hindbrain region produced abnormalities in brain development by disrupting cell cycle, Wnt signaling, and p53‐induced cell death of neuroepithelial cells (Dong & Kwan, 2020). Recent studies have also shown that GFAP‐specific YY1 deletion during end‐stage embryonic development caused phenotype abnormalities and severe motor deficits, suggesting a linkage to impaired cerebellar astrocyte maturation (Mockenhaupt et al, 2021).…”

“…Increased expression levels of multiple chemokines including Cxcl10 may facilitate intercellular communication between glia and neurons (Banisadr et al, 2005). CXCL10 was highly upregulated in both astrocytes and microglia of all brain regions in astrocytic YY1 cKO mice as well as YY1-knockdown astrocytic cultures (Figure 10), suggesting that astrocytes are responsible for the inflammatory phenotype in the brain (Mockenhaupt et al, 2021), at least in part by YY1 deficiency in astrocytes. CXCL10 upregulation is linked to neurodegenerative diseases (Xia et al, 2000) and induces neuronal injury by dysregulating mitochondrial function (Sui et al, 2006) and promoting a proinflammatory environment (Jiang, Huang, et al, 2021).…”

“…YY1 function in developmental stages of the brain has been previously studied (Dong & Kwan, 2020; He et al, 2007; Pajarillo et al, 2020; Zurkirchen et al, 2019). Recently, it has been reported that astrocyte‐specific YY1 deletion during the later stages of postnatal development in glial fibrillary acidic protein (GFAP)‐controlled YY1 conditional knockout (YY1 cKO) mice impaired astrocytic maturation and motor function along with apoptosis, and increased the expression of many inflammatory genes (Mockenhaupt et al, 2021).…”

“…In astrocytes, YY1 is highly expressed (Karki et al, 2014; Waters et al, 2019), but little is known as to whether astrocytic YY1 regulates brain function and astrocyte‐specific functions. Studies have shown that YY1 is dispensable during the early stages of astrocyte development but it is essential during late stages of brain development, which are governed by region‐specific interactions with neurons and for maintaining mature astrocytes in the adult brain (Mockenhaupt et al, 2021). Given that astrocytes are present throughout the entire CNS and perform critical functions (Farmer & Murai, 2017; Khakh & Sofroniew, 2015), the role of astrocytic YY1 in contributing to brain function is worthy of study.…”