Aberrant Development of the Suprachiasmatic Nucleus and Circadian Rhythms in Mice Lacking the Homeodomain Protein Six6
Aberrant Development of the Suprachiasmatic Nucleus and Circadian Rhythms in Mice Lacking the Homeodomain Protein Six6
复制标题
DOI：
10.1177/0748730412468084
复制
发表时间：
2013-02-01
影响因子：
3.5
通讯作者：
Mellon, Pamela L.
中科院分区：
文献类型：
--
作者：
Clark, Daniel D.;Gorman, Michael R.;Mellon, Pamela L.
哺乳动物下丘脑的视交叉上核（SCN）是外周和机体昼夜节律的中枢起搏器。这种下丘脑结构的发育依赖于整个胚胎发生过程中的遗传程序。我们研究了同源结构域转录因子Six6在SCN发育中的作用。我们首先表明，Six6 mRNA在小鼠SCN中具有昼夜节律调节。然后，我们描述了Six6基因缺失小鼠在各种光周期操作下的行为活动模式，并使用SCN特异性标记物对它们的下丘脑进行染色。Six6基因缺失小鼠表现出异常的昼夜节律行为模式，这表明SCN异常。光照重置节律的能力与视神经的存在与否相关，但所有Six6基因缺失小鼠都表现出不规则的节律。相比之下，视神经受损的野生型小鼠无论是否暴露于光照都保持规律的节律。通过对精氨酸加压素（AVP）、血管活性肠肽（VIP）和β - 半乳糖苷酶进行免疫组织化学分析，我们证明了所有Six6基因缺失小鼠都缺乏这些SCN标记物，无论是否存在视神经或部分昼夜节律。因此，Six6是SCN正常发育所必需的，并且尽管Six6基因缺失小鼠明显缺乏组织化学定义的SCN，但它们能够产生独立的（尽管是不规则的）昼夜节律。
The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is the central pacemaker for peripheral and organismal circadian rhythms. The development of this hypothalamic structure depends on genetic programs throughout embryogenesis. We have investigated the role of the homeodomain transcription factor Six6 in the development of the SCN. We first showed that Six6 mRNA has circadian regulation in the mouse SCN. We then characterized the behavioral activity patterns of Six6-null mice under various photoperiod manipulations and stained their hypothalami using SCN-specific markers. Six6-null mice display abnormal patterns of circadian behavior indicative of SCN abnormalities. The ability of light exposure to reset rhythms correlates with the presence or absence of optic nerves, but all Six6-null mice show irregular rhythms. In contrast, wild-type mice with crushed optic nerves maintain regular rhythms regardless of light exposure. Using immunohistochemistry for arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), and beta-galactosidase, we demonstrated the lack of these SCN markers in all Six6-null mice regardless of the presence of optic nerve or partial circadian rhythms. Therefore, Six6 is required for the normal development of the SCN, and the Six6-null mouse can mount independent, although irregular, circadian rhythms despite the apparent absence of a histochemically defined SCN.