KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors (RNA-Seq)

The 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 developing dorsal telencephalon (Kdm2bEmx1-deltaCxxC) to surprisingly discover that the size of Kdm2bEmx1-deltaCxxC hippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure. Kdm2bEmx1-deltaCxxC mice displayed prominent defects in spatial memory, motor learning and fear conditioning. The differentiation path of the developing Kdm2bEmx1-deltaCxxC hippocampus was greatly delayed, with significant amount of TBR2-expressing intermediate progenitors being stuck along the migratory 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 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. Comparative gene expression profiling analysis of RNA-seq data for P0 mouse cortex of control and Kdm2b-cKO(Emx1-deltaCxxC), and P0 mouse hippocampi of control and Rnf2-cKO.海马体（hippocampus）在学习与记忆过程中发挥核心作用。与大脑其他脑区类似，海马体的发育依赖模式形成、细胞增殖、分化与迁移的精准协同，且涉及细胞内在与外在双重调控机制。本研究通过遗传学手段，在发育中的背侧端脑（dorsal telencephalon）中敲除了KDM2B的染色质结合能力——KDM2B是多梳抑制复合体1（PRC1）变体的关键组分——构建了Kdm2bEmx1-ΔCxxC小鼠模型，却意外发现该模型小鼠的海马体，尤其是齿状回（dentate gyrus），体积显著缩小，细胞组分与结构均出现紊乱。Kdm2bEmx1-ΔCxxC小鼠在空间记忆、运动学习与恐惧条件反射方面均表现出显著缺陷。发育中Kdm2bEmx1-ΔCxxC小鼠海马体的分化通路大幅延迟，大量表达TBR2的中间前体细胞在迁移路径中发生滞留。对新生小鼠海马体及其前体细胞开展的转录组与染色质免疫沉淀研究显示，与干细胞干性维持相关的基因，尤其是经典Wnt信号通路组分，无法被PRC1与多梳抑制复合体2（PRC2）正常沉默。激活Wnt信号会干扰海马体神经发生，重现KDM2B缺失所诱导的表型。综上，本研究揭示了此前未被报道的、由KDM2B介导的基因沉默程序，该程序可调控细胞命运的逐步特化与细胞迁移，进而影响发育过程中海马体的形态发生。本研究同时对对照组与Kdm2b条件性敲除（Emx1-ΔCxxC）的P0（出生后0天）小鼠皮层、以及对照组与Rnf2条件性敲除的P0小鼠海马体的RNA测序（RNA-seq）数据进行了比较基因表达谱分析。