Institute of Anatomy I, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Institute of Anatomy II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
J Pineal Res. 2024 Aug;76(5):e12986. doi: 10.1111/jpi.12986.
This contribution reviews the role of inbred and transgenic mouse strains for deciphering the mammalian melatoninergic and circadian system. It focusses on the pineal organ as melatonin factory and two major targets of the melatoninergic system, the suprachiasmatic nuclei (SCN) and the hypophysial pars tuberalis (PT). Mammalian pinealocytes sharing molecular characteristics with true pineal and retinal photoreceptors synthesize and secrete melatonin into the blood and cerebrospinal fluid night by night. Notably, neuron-like connections exist between the deep pinealocytes and the habenular/pretectal region suggesting direct pineal-brain communication. Control of melatonin biosynthesis in rodents involves transcriptional regulation including phosphorylation of CREB and upregulation of mPer1. In the SCN, melatonin acts upon MT1 and MT2 receptors. Melatonin is not necessary to maintain the rhythm of the SCN molecular clockwork, but it has distinct effects on the synchronization of the circadian rhythm by light, facilitates re-entrainment of the circadian system to phase advances in the level of the SCN molecular clockwork by acting upon MT2 receptors and plays a stabilizing role in the circadian system as evidenced from locomotor activity recordings. While the effects in the SCN are subtle, melatonin is essential for PT functions. Via the MT1 receptor it drives the PT-intrinsic molecular clockwork and the retrograde and anterograde output pathways controlling seasonal rhythmicity. Although inbred and transgenic mice do not show seasonal reproduction, the pathways from the PT are fully intact if the animals are melatonin proficient. Thus, only melatonin-proficient strains are suited to investigate the circadian and melatoninergic systems.
这篇综述探讨了近交系和转基因小鼠在解析哺乳动物褪黑素能和生物钟系统中的作用。重点介绍了松果腺作为褪黑素工厂，以及褪黑素能系统的两个主要靶点，即视交叉上核（SCN）和垂体中间部（PT）。具有与真正的松果体和视网膜光感受器分子特征的哺乳动物松果体细胞夜夜合成并将褪黑素分泌到血液和脑脊液中。值得注意的是，深松果体细胞与缰核/前脑区之间存在神经元样连接，表明直接的松果体-脑通讯。啮齿动物褪黑素生物合成的调控涉及转录调控，包括 CREB 的磷酸化和 mPer1 的上调。在 SCN 中，褪黑素作用于 MT1 和 MT2 受体。褪黑素对于 SCN 分子生物钟节律的维持不是必需的，但它通过作用于 MT2 受体对光同步昼夜节律具有明显的作用，有助于通过 SCN 分子生物钟水平的相位提前重新同步生物钟系统，并通过在昼夜节律系统中发挥稳定作用，这一点从记录到的运动活动中可以得到证明。虽然 SCN 中的作用很细微，但褪黑素对于 PT 功能是必需的。通过 MT1 受体，它驱动 PT 内在的分子生物钟和控制季节性节律的逆行和顺行输出途径。尽管近交系和转基因小鼠没有表现出季节性繁殖，但如果动物具有褪黑素功能，PT 的途径是完全完整的。因此，只有褪黑素功能正常的品系才适合研究昼夜节律和褪黑素能系统。
