E-proteins encoded by Tcf3, Tcf4, and Tcf12 are class I basic helix-loop-helix (bHLH) transcription factors (TFs) that are thought to be widely expressed during development. However, their function in the developing brain, specifically in the telencephalon remains an active area of research. Our study examines for the first time if combined loss of two E-proteins (Tcf3 and Tcf12) influence distinct cell fates and oligodendrocyte development in the mouse telencephalon. We generated Tcf3/12 double conditional knockouts (dcKOs) using Olig2Cre/+ or Olig1Cre/+ to overcome compensatory mechanisms between E-proteins and to understand the specific requirement for Tcf3 and Tcf12 in the ventral telencephalon and during oligodendrogenesis. We utilized a combination of in situ hybridization, immunohistochemistry, and immunofluorescence to address development of the telencephalon and oligodendrogenesis at embryonic and postnatal stages in Tcf3/12 dcKOs. We show that the E-proteins Tcf3 and Tcf12 are expressed in progenitors of the embryonic telencephalon and throughout the oligodendrocyte lineage in the postnatal brain. Tcf3/12 dcKOs showed transient defects in progenitor cells with an enlarged medial ganglionic eminence (MGE) region which correlated with reduced generation of embryonic oligodendrocyte progenitor cells (OPCs) and increased expression of MGE interneuron genes. Postnatal Tcf3/12 dcKOs showed a recovery of OPCs but displayed a sustained reduction in mature oligodendrocytes (OLs). Interestingly, Tcf4 remained expressed in the dcKOs suggesting that it cannot compensate for the loss of Tcf3 and Tcf12. Generation of Tcf3/12 dcKOs with Olig1Cre/+ avoided the MGE morphology defect caused by Olig2Cre/+ but dcKOs still exhibited reduced embryonic OPCs and subsequent reduction in postnatal OLs. Our data reveal that Tcf3 and Tcf12 play a role in controlling OPC versus cortical interneuron cell fate decisions in MGE progenitors in addition to playing roles in the generation of embryonic OPCs and differentiation of postnatal OLs in the oligodendrocyte lineage.

中文翻译：

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小鼠端脑少突胶质细胞发育过程中对 Tcf3 和 Tcf12 的不同要求

Tcf3、Tcf4 和 Tcf12 编码的 E 蛋白是 I 类碱性螺旋-环-螺旋 (bHLH) 转录因子 (TF)，被认为在发育过程中广泛表达。然而，它们在发育中的大脑中的功能，特别是在端脑中的功能仍然是一个活跃的研究领域。我们的研究首次检验了两种 E 蛋白（Tcf3 和 Tcf12）的联合丢失是否会影响小鼠端脑中不同的细胞命运和少突胶质细胞的发育。我们使用 Olig2Cre/+ 或 Olig1Cre/+ 生成 Tcf3/12 双条件敲除 (dcKO)，以克服 E 蛋白之间的补偿机制，并了解腹侧端脑和少突胶质细胞发生过程中对 Tcf3 和 Tcf12 的具体要求。我们结合使用原位杂交、免疫组织化学和免疫荧光来解决 Tcf3/12 dcKO 胚胎和出生后阶段端脑和少突胶质细胞发育的问题。我们发现 E 蛋白 Tcf3 和 Tcf12 在胚胎端脑祖细胞和出生后大脑的整个少突胶质细胞谱系中表达。Tcf3/12 dcKOs 在祖细胞中显示出短暂的缺陷，具有扩大的内侧神经节隆起 (MGE) 区域，这与胚胎少突胶质祖细胞 (OPC) 生成减少和 MGE 中间神经元基因表达增加相关。出生后 Tcf3/12 dcKO 显示 OPC 恢复，但成熟少突胶质细胞 (OL) 持续减少。有趣的是，Tcf4 在 dcKO 中仍然表达，表明它无法补偿 Tcf3 和 Tcf12 的损失。使用 Olig1Cre/+ 生成 Tcf3/12 dcKO 避免了 Olig2Cre/+ 引起的 MGE 形态缺陷，但 dcKO 仍然表现出胚胎 OPC 减少以及随后出生后 OL 减少。我们的数据显示，Tcf3 和 Tcf12 除了在少突胶质细胞谱系中胚胎 OPC 的生成和出生后 OL 的分化中发挥作用外，还在 MGE 祖细胞中控制 OPC 与皮质中间神经元细胞命运决定中发挥作用。