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

The hippocampus plays major roles in learning and memory, and its formation requires precise coordination of patterning, cell proliferation, differentiation, and migration. Here we removed the chromatin-association capability of KDM2B in the progenitors of developing dorsal telencephalon (Kdm2b(∆CxxC)) to discover that Kdm2b(∆CxxC) hippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure. Kdm2b(∆CxxC) mice display prominent defects in spatial memory, motor learning and fear conditioning, resembling patients with KDM2B mutations. The migration and differentiation of neural progenitor cells is greatly impeded in the developing Kdm2b(∆CxxC) hippocampus. Mechanism studies reveal that Wnt signaling genes in developing Kdm2b(∆CxxC) hippocampi are de-repressed due to reduced enrichment of repressive histone marks by polycomb repressive complexes. Activating the Wnt signaling disturbs hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveil a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of the hippocampus.