Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons
Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons
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DOI：
10.1073/pnas.1210479109
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发表时间：
2012-11-06
影响因子：
11.1
通讯作者：
Green, Michael R.
中科院分区：
文献类型：
--
作者：
Wang, Shu-Zong;Ou, Jianhong;Green, Michael R.
转录激活因子5（Activating Transcription Factor 5，ATF 5）是ATF/cAMP反应元件结合转录因子家族的一员，由碱性亮氨酸拉链蛋白（basic region leucine zipper protein）组成，其成员介导多种转录调控功能。ATF 5具有良好的促存活活性，并且已经发现在几种人类癌症，特别是胶质母细胞瘤中过表达。然而，ATF 5在发育和正常生理学中的作用尚不清楚。在这里，我们解决这个问题，通过推导和表征纯合子Atf 5基因敲除小鼠。我们发现，Atf 5（-/-）幼鼠死亡的哺乳期，这是一致的，如下所述，嗅觉缺陷导致竞争性哺乳赤字。我们发现，Atf 5是高度表达的嗅觉感觉神经元（OSNs）的主要嗅上皮从胚胎期11.5到成年。OSN特异性标记的免疫染色实验表明，ATF 5在一些未成熟的OSN和所有成熟的OSN中表达。表达谱分析和免疫染色实验表明，Atf 5的损失导致大量的减少，在成熟的OSN的分化缺陷和诱导细胞凋亡。Atf 5在神经前体细胞中的异位表达诱导多个OSN特异性基因的表达总的来说，我们的研究结果表明一个模型，其中Atf 5首先在不成熟的OSN中表达，并且所产生的ATF 5的功能是促进分化为成熟的OSN。因此，ATF 5是OSN终末分化和存活所必需的。
Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element-binding family of transcription factors, which compose a large group of basic region leucine zipper proteins whose members mediate diverse transcriptional regulatory functions. ATF5 has a well-established prosurvival activity and has been found to be overexpressed in several human cancers, in particular glioblastoma. However, the role(s) of ATF5 in development and normal physiology are unknown. Here we address this issue by deriving and characterizing homozygous Atf5 knockout mice. We find that Atf5(-/-) pups die neonatally, which, as explained below, is consistent with an olfactory defect resulting in a competitive suckling deficit. We show that Atf5 is highly expressed in olfactory sensory neurons (OSNs) in the main olfactory epithelium starting from embryonic stage 11.5 through adulthood. Immunostaining experiments with OSN-specific markers reveal that ATF5 is expressed in some immature OSNs and in all mature OSNs. Expression profiling and immunostaining experiments indicate that loss of Atf5 leads to a massive reduction in mature OSNs resulting from a differentiation defect and the induction of apoptosis. Ectopic expression of Atf5 in neural progenitor cells induces expression of multiple OSN-specific genes. Collectively, our results suggest a model in which Atf5 is first expressed in immature OSNs and the resultant ATF5 functions to promote differentiation into mature OSNs. Thus, ATF5 is required for terminal differentiation and survival of OSNs.