Lef1-dependent hypothalamic neurogenesis inhibits anxiety.
Lef1-dependent hypothalamic neurogenesis inhibits anxiety.
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LEF1依赖性下丘脑神经发生抑制焦虑。
DOI：
10.1371/journal.pbio.2002257
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发表时间：
2017-08
期刊：
影响因子：
9.8
通讯作者：
Dorsky RI
中科院分区：
文献类型：
--
作者：
Xie Y;Kaufmann D;Moulton MJ;Panahi S;Gaynes JA;Watters HN;Zhou D;Xue HH;Fung CM;Levine EM;Letsou A;Brennan KC;Dorsky RI
虽然先天行为在整个动物界都是保守的，但尚不清楚共同的信号通路是否调节不同生物体中介导这些行为的神经元群的发育。在这里，我们证明 Wnt/β-连环蛋白效应器 Lef1 是斑马鱼和小鼠抗焦虑下丘脑神经元分化所必需的，尽管这两个物种之间 Lef1 依赖性基因和神经元的身份不同。我们进一步表明，斑马鱼和果蝇在各自的神经内分泌器官中具有共同的 Lef1 依赖性基因表达，这与小鼠中存在分歧的保守途径一致。最后，来自斑马鱼和小鼠的 Lef1 依赖性基因的直向同源物在狨猴和人类中显示出高度相关的下丘脑表达，表明灵长类动物中 2 个平行的抗焦虑途径的共同调节。这些发现表明，在进化过程中，转录因子可以通过多种机制发挥作用，产生共同的行为输出，并且 Lef1 调节回路发育，这对于调节多种动物物种的焦虑至关重要。人类、小鼠、鱼类甚至苍蝇都会表现出类似焦虑的行为，尽管它们的大脑解剖结构差异很大。这项研究揭示了这些不同动物的另一个共同点：它们共同行为的分子起源。小鼠和斑马鱼的基因敲除实验表明，分子信号 Wnt 通过转录因子 Lef1 发挥作用，抑制这两个物种的焦虑。该通路是高度保守的大脑区域（下丘脑）形成抗焦虑神经元所必需的。然而，从那时起，这个过程就出现了分歧。在鱼中，该通路会触发包括促肾上腺皮质激素释放激素结合蛋白（crhbp）在内的基因，但在小鼠中，相同的通路会激活不同的基因，即黑色素原浓缩激素（Pmch）。相比之下，果蝇激活 crhbp，与斑马鱼类似。此外，CRHBP 和 PMCH 在灵长类下丘脑中表现出异常协调的表达，表明它们可能在 Wnt 和 Lef1 下游共同作用来调节人类行为。这项工作揭示了一个令人惊讶的发现，即保守的信号通路可以在进化过程中通过不同的大脑回路调节常见的行为输出。
While innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. Here, we demonstrate that the Wnt/ß-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse. Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species. Humans, mice, fish, and even flies exhibit anxiety-like behavior despite the fact that their brain anatomy varies widely. This study reveals another common thread that runs through these diverse animals: the molecular origins of their shared behavior. Gene knockout experiments in mouse and zebrafish show that the molecular signal Wnt acts through the transcription factor Lef1 to inhibit anxiety in both species. The pathway is required for formation of anxiolytic neurons in a highly conserved brain region, the hypothalamus. From there, however, the process diverges. In the fish, the pathway triggers genes including corticotropin-releasing hormone binding protein (crhbp), but in mice the same pathway calls into action a different gene, Pro-melanin concentrating hormone (Pmch). By comparison, the fruit fly Drosophila activates crhbp, similar to zebrafish. Furthermore, CRHBP and PMCH show extraordinarily coordinated expression in the primate hypothalamus, indicating that they may act together downstream of Wnt and Lef1 to regulate human behavior. This work reveals the surprising finding that conserved signaling pathways can regulate common behavioral outputs through diverse brain circuits during evolution.
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β-catenin通过DICER1/microRNA调节介导了应力弹性。
影响因子：
64.8
作者：
Dias, Caroline;Feng, Jian;Sun, Haosheng;Shao, Ning yi;Mazei-Robison, Michelle S.;Damez-Werno, Diane;Scobie, Kimberly;Bagot, Rosemary;LaBonte, Benoit;Ribeiro, Efrain;Liu, XiaoChuan;Kennedy, Pamela;Vialou, Vincent;Ferguson, Deveroux;Pena, Catherine;Calipari, Erin S.;Koo, Ja Wook;Mouzon, Ezekiell;Ghose, Subroto;Tamminga, Carol;Neve, Rachael;Shen, Li;Nestler, Eric J.
通讯作者：
Nestler, Eric J.
影响因子：
16.6
作者：
González JA;Iordanidou P;Strom M;Adamantidis A;Burdakov D
通讯作者：
Burdakov D
DOI：
10.1016/j.bbrc.2006.07.124
发表时间：
2006-09-29
影响因子：
3.1
作者：
Boehm, Johann;Sustmann, Claudio;Kohlhase, Juergen
通讯作者：
Kohlhase, Juergen
影响因子：
2.7
作者：
Dorsky, RI;Sheldahl, LC;Moon, RT
通讯作者：
Moon, RT
影响因子：
4.6
作者：
Duncan, Robert N.;Xie, Yuanyuan;Dorsky, Richard I.
通讯作者：
Dorsky, Richard I.