How mammalian neuronal identity is progressively acquired and reinforced during development is not understood. We have previously shown that loss of RP58 (ZNF238, ZBTB18), a BTB/POZ and zinc finger containing transcription factor, in the mouse brain leads to microcephaly, corpus callosum agenesis, cerebellum hypoplasia and that it is required for normal neuronal differentiation. The transcriptional programs regulated by RP58 during this process are not known. Here, we report for the first time that in embryonic mouse neocortical neurons a complex set of genes normally expressed in other cell types, such as those from mesoderm derivatives, must be actively repressed in vivo and that RP58 is a critical regulator of these repressed transcriptional programs. Importantly, the GSEA analyses of these transcriptional programs indicate that repressed genes include distinct sets of genes significantly associated with glioma progression and/or pluripotency. We also demonstrate that reintroducing RP58 in glioma stem cells not only leads to aspects of neuronal differentiation but also to loss of stem cell characteristics, including loss of stem cell markers and decrease in stem cell self-renewal capacities. Thus, RP58 acts as an in vivo master guardian of the neuronal identity transcriptome and its function may be required to prevent brain disease development including glioma progression.

中文翻译：

---

RP58 抑制与发育中神经元中的非神经元细胞身份和胶质母细胞瘤亚型相关的转录程序

哺乳动物神经元身份如何在发育过程中逐渐获得和加强尚不清楚。我们之前已经表明，小鼠大脑中 RP58（ZNF238、ZBTB18）（一种 BTB/POZ 和含有锌指的转录因子）的缺失会导致小头畸形、胼胝体发育不全、小脑发育不全，并且它是正常神经元分化所必需的。在此过程中由 RP58 调节的转录程序尚不清楚。在这里，我们首次报告在胚胎小鼠新皮质神经元中，一组通常在其他细胞类型中表达的复杂基因，例如来自中胚层衍生物的基因，必须在体内被积极抑制并且 RP58 是这些被抑制的转录程序的关键调节因子。重要的是，这些转录程序的 GSEA 分析表明，受抑制的基因包括与神经胶质瘤进展和/或多能性显着相关的不同基因组。我们还证明，在神经胶质瘤干细胞中重新引入 RP58 不仅会导致神经元分化的各个方面，还会导致干细胞特征的丧失，包括干细胞标志物的丧失和干细胞自我更新能力的降低。因此，RP58 充当神经元身份转录组的体内主要监护人，其功能可能是预防脑疾病发展（包括神经胶质瘤进展）所必需的。