DOT1L deletion impairs the development of cortical Parvalbumin-expressing interneurons

Our group has reported that the histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion of Dot1l in MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered postmitotic differentiation/maturation. Assessment of DOT1L role in the development of cortical interneurons at E14.5.本研究团队此前已有报道，组蛋白甲基转移酶DOT1L（histone methyltransferase DOT1L）是正常皮层板发育以及谷氨酸能神经元分层分布所必需的，然而其在皮层中间神经元发育中的具体作用迄今尚未得到探索。本研究证实，DOT1L以细胞自主性方式调控中间神经元的发育。在内侧神经节隆起（MGE）来源的中间神经元前体细胞中敲除Dot1l，会导致出生后第0天（P0）的皮层板内γ-氨基丁酸能（GABAergic）中间神经元总数减少且分布异常。此外，我们在出生后第21天（P21）的皮层与纹状体中观察到γ-氨基丁酸能中间神经元的比例发生改变，其中表达小白蛋白（PVALB）的中间神经元数量显著降低。综上，本研究结果表明，DOT1L缺失导致的皮层中间神经元数量减少，源于有丝分裂后分化与成熟过程的异常。本研究还评估了胚胎第14.5天（E14.5）时DOT1L对皮层中间神经元发育的调控作用。