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Reduced VIP Expression Affects Circadian Clock Function in VIP-IRES-CRE Mice (JAX 010908).
Journal of Biological Rhythms ( IF 2.9 ) Pub Date : 2020-05-28 , DOI: 10.1177/0748730420925573
Deborah A M Joye 1 , Kayla E Rohr 1 , Danielle Keller 1 , Thomas Inda 1 , Adam Telega 1 , Harshida Pancholi 1 , Vania Carmona-Alcocer 1 , Jennifer A Evans 1
Affiliation  

Circadian rhythms are programmed by the suprachiasmatic nucleus (SCN), which relies on neuropeptide signaling to maintain daily timekeeping. Vasoactive intestinal polypeptide (VIP) is critical for SCN function, but the precise role of VIP neurons in SCN circuits is not fully established. To interrogate their contribution to SCN circuits, VIP neurons can be manipulated specifically using the DNA-editing enzyme Cre recombinase. Although the Cre transgene is assumed to be inert by itself, we find that VIP expression is reduced in both heterozygous and homozygous adult VIP-IRES-Cre mice (JAX 010908). Compared with wild-type mice, homozygous VIP-Cre mice display faster reentrainment and shorter free-running period but do not become arrhythmic in constant darkness. Consistent with this phenotype, homozygous VIP-Cre mice display intact SCN PER2::LUC rhythms, albeit with altered period and network organization. We present evidence that the ability to sustain molecular rhythms in the VIP-Cre SCN is not due to residual VIP signaling; rather, arginine vasopressin signaling helps to sustain SCN function at both intracellular and intercellular levels in this model. This work establishes that the VIP-IRES-Cre transgene interferes with VIP expression but that loss of VIP can be mitigated by other neuropeptide signals to help sustain SCN function. Our findings have implications for studies employing this transgenic model and provide novel insight into neuropeptide signals that sustain daily timekeeping in the master clock.



中文翻译:

VIP 表达减少会影响 VIP-IRES-CRE 小鼠的昼夜节律功能 (JAX 010908)。

昼夜节律由视交叉上核 (SCN) 编程,它依靠神经肽信号来维持日常计时。血管活性肠多肽 (VIP) 对 SCN 功能至关重要,但 VIP 神经元在 SCN 回路中的确切作用尚未完全确定。为了探究它们对 SCN 电路的贡献,可以使用 DNA 编辑酶 Cre 重组酶专门操纵 VIP 神经元。尽管 Cre 转基因本身被认为是惰性的,但我们发现 VIP 表达在杂合和纯合成年 VIP-IRES-Cre 小鼠 (JAX 010908) 中均降低。与野生型小鼠相比,纯合子 VIP-Cre 小鼠表现出更快的再牵引和更短的自由奔跑期,但在持续的黑暗中不会出现心律失常。与此表型一致,纯合 VIP-Cre 小鼠显示完整的 SCN PER2:: LUC 节律,尽管周期和网络组织有所改变。我们提出的证据表明,在 VIP-Cre SCN 中维持分子节律的能力不是由于残留的 VIP 信号传导。相反,精氨酸加压素信号有助于在该模型中维持细胞内和细胞间水平的 SCN 功能。这项工作确定了 VIP-IRES-Cre 转基因干扰 VIP 表达,但其他神经肽信号可以减轻 VIP 的损失,以帮助维持 SCN 功能。我们的研究结果对采用这种转基因模型的研究具有重要意义,并为维持主时钟中的日常计时的神经肽信号提供了新的见解。相反,精氨酸加压素信号有助于在该模型中维持细胞内和细胞间水平的 SCN 功能。这项工作确定了 VIP-IRES-Cre 转基因干扰 VIP 表达,但其他神经肽信号可以减轻 VIP 的损失,以帮助维持 SCN 功能。我们的研究结果对采用这种转基因模型的研究具有重要意义,并为维持主时钟中的日常计时的神经肽信号提供了新的见解。相反,精氨酸加压素信号有助于在该模型中维持细胞内和细胞间水平的 SCN 功能。这项工作确定了 VIP-IRES-Cre 转基因干扰 VIP 表达,但其他神经肽信号可以减轻 VIP 的损失,以帮助维持 SCN 功能。我们的研究结果对采用这种转基因模型的研究具有重要意义,并为维持主时钟中的日常计时的神经肽信号提供了新的见解。

更新日期:2020-05-28
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