KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors

Abstract

AbstractThe hippocampus plays major roles in learning and memory. Similar to other parts of the brain, the development of hippocampus requires precise coordination of patterning, cell proliferation, differentiation, and migration, with both cell-intrinsic and extrinsic mechanisms involved. Here we genetically removed the chromatin-association capability of KDM2B - a key component of the variant Polycomb repressive complex 1 (PRC1) - in the progenitors of developing dorsal telencephalon (Kdm2bΔCxxC) to surprisingly discover that the size ofKdm2bΔCxxChippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure.Kdm2bΔCxxCmice displayed prominent defects in spatial memory, motor learning and fear conditioning. The differentiation trajectory of the developingKdm2bΔCxxChippocampus was greatly delayed, with a significant amount of TBR2-expressing intermediate progenitors stuck along the migratory/differentiation path. Transcriptome and chromatin immunoprecipitation studies of neonatal hippocampi and their progenitors indicated that genes implicated in stemness maintenance, especially components of canonical Wnt signaling, could not be properly silenced by PRC1 and PRC2. Activating the Wnt signaling disturbed hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveiled a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of hippocampus during development.Graphic AbstractLoss of KDM2B-CxxC reduces repressive histone modifications – H2AK119ub and H3K27me3 - on key Wnt signal genes, hence leading to the block of their attenuation over time. Hampered differentiation and migration of hippocampal progenitors leads to hippocampal agenesis.