Zhx2 maintains neural stem/progenitor cell homeostasis via the CELSR1/Wnt/ROCK axis in the mouse brain

Abnormal proliferation and differentiation of neural stem/progenitor cells (NSPCs) can lead to defects in neural development. However, the key regulators remain undeterminded. Here, we identify the transcription factor zinc fingers and homeoboxes 2 (Zhx2) as a crucial player orchestrating the proliferation and differentiation of NSPCs. Zhx2 conditional deletion in nestin-positive cells (Zhx2?/?) resulted in a reduction in NSPC number, reduced proliferation, and promoted NSPC differentiation. Zhx2?/? mice exhibited enlarged lateral ventricles, smaller hippocampi, anxiety, recognition and memory defects, and motor coordination disorders. Transcriptomic analysis revealed CELSR1, a transmembrane calcium adhesive protein, as a direct downstream target of Zhx2 in the Wnt/ROCK pathway. Our findings elucidate Zhx2's role in brain morphological development and regulation of NSPC proliferation and differentiation, suggesting a promising strategy for neurodevelopmental disorders. Overall design: RNA-seq profiling of Zhx2+/+ and Zhx2?/? mice from the SVZ