Human-biased MEIS1 expression by a promoter noncoding RNA regulates neural stem cell proliferation.

Whereas primate-specific genes are known to drive human evolution, conserved genes also play critical roles in defining species-specific traits. This study identifies MEIS1 as a key conserved gene with significantly higher expression in human radial glia compared with those in mice. Our functional analysis revealed that MEIS1 knockdown (KD) in human cerebral organoids leads to premature neural differentiation. Conversely, MEIS1 overexpression in the mouse brain significantly increases the abundance of neural progenitor cells (NPCs). By investigating a noncoding RNA (ncRNA) partner derived from the MEIS1 promoter, we demonstrated that its KD triggers MEIS1 down-regulation, markedly reducing NPC proliferative capacity. RNA-sequencing further indicated that MEIS1 regulates genes involved in cholesterol biogenesis. Specifically, forced expression of DHCR7, a MEIS1-target gene, rescued both the proliferative deficits and the reduction in primary cilia length induced by MEIS1 KD. These findings suggest that ncRNA-mediated regulatory mechanism for the conserved MEIS1 coordinates primary cilia morphology and cholesterol metabolism. This coordination is essential for maintaining long-term NPC properties, ultimately contributing to the evolutionary expansion of the human cerebral cortex.