Genetic and epigenetic factors contribute to the development of the spinal cord. Failure in correct exertion of the developmental programs, including neurulation, neural tube closure and neurogenesis of the diverse spinal cord neuronal subtypes results in defects of variable severity. We here report on the histone methyltransferase Disruptor of Telomeric 1 Like (DOT1L), which mediates histone H3 lysine 79 (H3K79) methylation. Conditional inactivation of DOT1L using Wnt1-cre as driver (Dot1l-cKO) showed that DOT1L expression is essential for spinal cord neurogenesis and localization of diverse neuronal subtypes, similar to its function in the development of the cerebral cortex and cerebellum. Transcriptome analysis revealed that DOT1L deficiency favored differentiation over progenitor proliferation. Dot1l-cKO mainly decreased the numbers of dI1 interneurons expressing Lhx2. In contrast, Lhx9 expressing dI1 interneurons did not change in numbers but localized differently upon Dot1l-cKO. Similarly, loss of DOT1L affected localization but not generation of dI2, dI3, dI5, V0 and V1 interneurons. The resulting derailed interneuron patterns might be responsible for increased cell death, occurrence of which was restricted to the late developmental stage E18.5. Together our data indicate that DOT1L is essential for subtype-specific neurogenesis, migration and localization of dorsal and ventral interneurons in the developing spinal cord, in part by regulating transcriptional activation of Lhx2.

中文翻译：

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发育中的脊髓中中间神经元的分化和定位取决于 DOT1L 的表达。

遗传和表观遗传因素有助于脊髓的发育。发育程序（包括不同脊髓神经元亚型的神经形成、神经管闭合和神经发生）的正确发挥失败会导致不同严重程度的缺陷。我们在此报告端粒 1 样组蛋白甲基转移酶干扰素 (DOT1L)，它介导组蛋白 H3 赖氨酸 79 (H3K79) 甲基化。使用 Wnt1-cre 作为驱动器条件性灭活 DOT1L (Dot1l-cKO) 表明，DOT1L 表达对于脊髓神经发生和不同神经元亚型的定位至关重要，类似于其在大脑皮层和小脑发育中的功能。转录组分析显示，DOT1L 缺陷有利于分化而不是祖细胞增殖。Dot1l-cKO 主要减少表达 Lhx2 的 dI1 中间神经元的数量。相比之下，表达 dI1 中间神经元的 Lhx9 在数量上没有变化，但在 Dot1l-cKO 上的定位不同。同样，DOT1L 的缺失影响定位，但不影响 dI2、dI3、dI5、V0 和 V1 中间神经元的生成。由此产生的脱轨中间神经元模式可能导致细胞死亡增加，其发生仅限于发育后期 E18.5。我们的数据共同表明，DOT1L 对于发育中的脊髓中背侧和腹侧中间神经元的亚型特异性神经发生、迁移和定位至关重要，部分是通过调节 Lhx2 的转录激活来实现的。