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GSX2 Regulates Progenitor Maturation and Regional Identity Through Transcriptional Repression in the Developing Basal Ganglia [ATAC-seq]

ABSTRACT: Transgenic mouse models have demonstrated the critical role of the homeodomain transcription factor Genetic-Screened Homeobox 2 (‍‍Gsx2) in the developing basal ganglia. However, the technical limitations of the existing in vivo approaches, such as progenitor heterogeneity and lack of temporal resolution, have impeded the investigation of direct regulatory targets . This study engineered a Dox-inducible human embryonic stem cell (‍‍hESC) line to investigate the function of GSX2 protein in directed differentiation cultures that model developing lateral ganglionic eminence-like (LGE-like) progenitors. Transcriptomic, chromatin accessibility, and genomic binding studies revealed that GSX2: (1) binds to both high- and low-accessibility chromatin using varying binding site preferences; (‌‌‌‌2) alters chromatin accessibility largely through indirect mechanisms; (3) functions primarily as a transcriptional repressor; and (4) regulates key conserved target genes of both progenitor maturation and regional specification. These results provide insight into the key regulatory roles and targets of GSX2, thereby establishing a new tractable experimental system to investigate basal ganglia development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306350 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate. The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate.

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GSX2 Regulates Progenitor Maturation and Regional Identity Through Transcriptional Repression in the Developing Basal Ganglia [ATAC-seq]

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