GLIS3 is a key transcriptional regulator of astrocyte differentiation in human neural stem cells

Abstract

Abstract Astrocytes play central role in regulation of neural homeostasis and are increasingly implicated in the pathogenesis of neurodegenerative disease. Emerging evidence links the transcription factor GLIS3 -/- to several neurological disorders and to astrocyte biology; however, its precise role in astrocytes remains unclear. Here, we define GLIS3 -/- as a critical regulator of astrocyte differentiation and gene expression. We first show that GLIS3 -/- is robustly expressed in mouse-derived astrocytes, as assessed by RT-qPCR and immunofluorescence. Using GLIS3-knockout human embryonic stem cells (hESCs), we further demonstrate that loss of GLIS3 -/- markedly impairs astrocyte differentiation, evidenced by reduced expression of canonical astrocyte markers. Conversely, exogenous GLIS3 -/- restores the induction of astrocyte-specific genes, establishing a critical role for GLIS3 -/- in astrocyte lineage differentiation. Integrative transcriptomic and cistromic analyses revealed that GLIS3 -/- directly controls a core astrocyte transcriptional program, including GFAP , SLC1A2 , NFIA , and ATF3 , and acts in concert with lineage-determining factors such as STAT3, NFIA, and SOX9. Pathway analysis further identifies GLIS3-dependent regulation of multiple genes, including SLC1A2 , GRIA4 , GRIA2 , SLC38A2 , and KCNJ10 , with roles in glutamate and potassium homeostasis, synaptic transmission, and synapse formation, processes essential for brain function and frequently disrupted in neurological disease. Together, these findings position GLIS3 -/- as an upstream regulator of astrocyte identity and function and suggest that its dysregulation may contribute to astrocyte-mediated neurodegenerative mechanisms. GLIS3 -/- therefore emerges as a potential therapeutic target in astrocyte-associated neurological disorders.

The authors' abstract, as published at the source. Cellular and Molecular Life Sciences, 2026 · DOI ↗