Foxa2 and Pet1 Direct and Indirect Synergy Drive Serotonergic Neuronal Differentiation.
Foxa2 and Pet1 Direct and Indirect Synergy Drive Serotonergic Neuronal Differentiation.
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DOI：
10.3389/fnins.2022.903881
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发表时间：
2022
影响因子：
4.3
通讯作者：
Mazzoni EO
中科院分区：
文献类型：
--
作者：
Aydin B;Sierk M;Moreno-Estelles M;Tejavibulya L;Kumar N;Flames N;Mahony S;Mazzoni EO
通过强制表达转录因子（TF）进行的神经元编程为再生医学的临床应用带来了希望。然而，转录因子在基因组上协调其活动并控制不同神经元命运的机制仍然不清楚。利用胚胎干细胞的直接神经元编程，我们剖析了一系列转录因子对特定神经元调节程序的贡献。我们解构了 Ascl1-Lmx1b-Foxa2-Pet1 TF 组合，该组合已被证明可以产生血清素能神经元，并发现将 TF 逐步添加到 Ascl1 可以将神经元命运转化为弥漫性单胺能神经元。先锋因子 Foxa2 的添加会抑制 Phox2b，从而诱导血清素命运，类似于体内调节网络。 Foxa2 和 Pet1 似乎协同作用，上调血清素的命运。 Foxa2 和 Pet1 与一小部分基因组区域共同结合，但大部分与不同的调控位点结合。与其他编程 TF 的组合绑定活动相比，Pet1 并没有严格遵循 Foxa2 先驱。这些发现凸显了制定可概括的规则来描述对不同神经元亚型进行编程的 TF 组合的行为所面临的挑战。
Neuronal programming by forced expression of transcription factors (TFs) holds promise for clinical applications of regenerative medicine. However, the mechanisms by which TFs coordinate their activities on the genome and control distinct neuronal fates remain obscure. Using direct neuronal programming of embryonic stem cells, we dissected the contribution of a series of TFs to specific neuronal regulatory programs. We deconstructed the Ascl1-Lmx1b-Foxa2-Pet1 TF combination that has been shown to generate serotonergic neurons and found that stepwise addition of TFs to Ascl1 canalizes the neuronal fate into a diffuse monoaminergic fate. The addition of pioneer factor Foxa2 represses Phox2b to induce serotonergic fate, similar to in vivo regulatory networks. Foxa2 and Pet1 appear to act synergistically to upregulate serotonergic fate. Foxa2 and Pet1 co-bind to a small fraction of genomic regions but mostly bind to different regulatory sites. In contrast to the combinatorial binding activities of other programming TFs, Pet1 does not strictly follow the Foxa2 pioneer. These findings highlight the challenges in formulating generalizable rules for describing the behavior of TF combinations that program distinct neuronal subtypes.
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影响因子：
4.3
作者：
Kakumanu A;Velasco S;Mazzoni E;Mahony S
通讯作者：
Mahony S
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
Pet-1 在生命的不同阶段都需要来调节血清素能功能。
影响因子：
25
作者：
Liu, Chen;Maejima, Takashi;Wyler, Steven C.;Casadesus, Gemma;Herlitze, Stefan;Deneris, Evan S.
通讯作者：
Deneris, Evan S.
基于胚胎干细胞的发展转录程序的映射。
影响因子：
48
作者：
Mazzoni, Esteban O.;Mahony, Shaun;Iacovino, Michelina;Morrison, Carolyn A.;Mountoufaris, George;Closser, Michael;Whyte, Warren A.;Young, Richard A.;Kyba, Michael;Gifford, David K.;Wichterle, Hynek
通讯作者：
Wichterle, Hynek
影响因子：
5.2
作者：
Iacovino, Michelina;Bosnakovski, Darko;Fey, Holger;Rux, Danielle;Bajwa, Gagan;Mahen, Elisabeth;Mitanoska, Ana;Xu, Zhaohui;Kyba, Michael
通讯作者：
Kyba, Michael