BBX maintains mammalian brain development by repressing p53-mediated p21 expression.

Abstract

Brain development requires coordinated regulation of neural stem cell (NSC) proliferation, differentiation, and neuronal migration. Here, we identify bobby sox homolog (BBX), a nuclear HMG box domain-containing protein enriched in mouse embryonic cortical germinal zones, as a regulator of corticogenesis. In the embryonic cortex, BBX depletion reduces SOX2-expressing NSCs, promotes premature cell-cycle exit, disrupts cortical cell positioning, causes abnormal clustering of newborn neurons, and impairs migratory neuron morphology. RNA-seq and public ChIP-seq analyses, together with biochemical assays, show that BBX interacts with p53 and suppresses p53-dependent p21 expression. Consistent with activation of the p21 pathway, BBX knockdown increases premature cell-cycle exit and senescence-associated features, including γH2AX accumulation and senescence-associated gene expression. Co-depletion of p21 rescues BBX knockdown-induced defects in NSC maintenance, neuronal distribution, and morphology. In line with this, depletion of retinoblastoma protein (RB), a major mediator of p21-dependent senescence, restores abnormal cortical cell distribution. These findings indicate that BBX maintains normal cortical development by restraining the p53-p21-RB axis, thereby preventing premature cell-cycle exit and senescence in developing neural cells.