Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis
Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis
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DOI：
10.15252/embj.201490061
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发表时间：
2015-04-01
期刊：
影响因子：
11.4
通讯作者：
Calegari, Federico
中科院分区：
文献类型：
--
作者：
Artegiani, Benedetta;Domingues, Antonio M. de Jesus;Calegari, Federico
主要的努力投入到表征控制神经干细胞增殖的因素。在哺乳动物皮质发生过程中，我们的研究小组已经确定了一小部分基因，这些基因在神经干细胞向神经原性分裂的转换中瞬时下调，并在新生神经元中重新诱导。在这些开关基因中，我们发现了Tox，一种迄今为止在神经系统中具有未知作用的转录因子。在这里，我们调查的作用，毒素在皮质的表达特征在组织，细胞和时间水平。我们发现Tox受钙调神经磷酸酶/Nfat信号转导的调节。此外，我们结合DNA腺嘌呤甲基转移酶鉴定（DamID）和深度测序来表征Tox的染色质结合特性，包括其基序和下游转录靶点，包括Sox 2，Tbr 2，Prox 1和其他关键因子。最后，我们在发育中的大脑中操纵Tox，并验证了其在促进神经干细胞增殖和新生神经元轴突生长中的多种作用。我们的数据为研究Tox在其他组织中的作用提供了宝贵的资源，并突出了大脑发育中的一个新的关键角色。
Major efforts are invested to characterize the factors controlling the proliferation of neural stem cells. During mammalian cortico-genesis, our group has identified a small pool of genes that are transiently downregulated in the switch of neural stem cells to neurogenic division and reinduced in newborn neurons. Among these switch genes, we found Tox, a transcription factor with hitherto uncharacterized roles in the nervous system. Here, we investigated the role of Tox in corticogenesis by characterizing its expression at the tissue, cellular and temporal level. We found that Tox is regulated by calcineurin/Nfat signalling. Moreover, we combined DNA adenine methyltransferase identification (DamID) with deep sequencing to characterize the chromatin binding properties of Tox including its motif and downstream transcriptional targets including Sox2, Tbr2, Prox1 and other key factors. Finally, we manipulated Tox in the developing brain and validated its multiple roles in promoting neural stem cell proliferation and neurite outgrowth of newborn neurons. Our data provide a valuable resource to study the role of Tox in other tissues and highlight a novel key player in brain development.