Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland.
Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
BMC Genomics. 2017 Sep 27;18(1):757. doi: 10.1186/s12864-017-4084-9.
In the domestic dog, corpora lutea (CL) are the only source of progesterone (P4), both in pregnant and non-pregnant cycles because there is no placental steroidogenesis. The absence of an endogenous luteolysin in absence of pregnancy results in long-lasting physiological pseudopregnancy, strongly contrasting with the acute luteolysis observed prepartum. The underlying biological mechanisms and the involvement of P4 signalling remain, however, not fully understood. Therefore, here, next-generation sequencing (RNA-Seq) was performed on CL from the late luteal phase and compared with normally luteolyzing CL collected at the prepartum P4 decrease.
The contrast "luteal regression over luteolysis" yielded 1595 differentially expressed genes (DEG). The CL in late luteal regression were predominantly associated with functional terms linked to extracellular matrix (p = 5.52e-05). Other terms related to transcriptional activity (p = 2.45e-04), and steroid hormone signalling (p = 2.29e-04), which were more highly represented in late regression than during luteolysis. The prepartum luteolysis was associated with immune inflammatory responses (p = 2.87e-14), including acute-phase reaction (p = 4.10e-06). Immune system-related events were also more highly represented in CL derived from normal luteolysis (p = 7.02e-04), compared with those from dogs in which luteolysis was induced with an antigestagen (1480 DEG in total). Additionally, the withdrawal of P4 at mid-gestation resulted in 92 DEG; over-represented terms enriched in antigestagen-treated dogs were related to the inflammatory response (p = 0.005) or response to IL1 (p = 7.29e-05). Terms related to proliferation, e.g., centrosome organization (p = 0.002) and steroid metabolic processes (p = 0.001), prevailed at mid-gestation. Thereby, our results revealed the nature of luteotropic effects of P4 within canine CL. It appears that, even though they result in diminished steroidogenic output, the effect of antigestagens is more related to the withdrawal of P4 support than to the PGF2alpha-related inflammatory reaction observed at physiological parturition.
We report the differential gene expression associated with maintenance and cessation of luteal function in pregnant and non-pregnant dogs. Based on the differentially expressed genes, we indicate functional pathways and gene networks that are potentially involved in the underlying endocrine and molecular mechanisms. This study establishes future research directions that may be helpful in understanding some of the clinical conditions, such as luteal insufficiency, associated with negative pregnancy outcome in dogs.
在犬中，黄体（CL）是孕激素（P4）的唯一来源，无论是在怀孕还是非怀孕周期，因为没有胎盘类固醇生成。在没有怀孕的情况下，缺乏内源性黄体溶解素会导致持久的生理性假性怀孕，与分娩前观察到的急性黄体溶解形成鲜明对比。然而，潜在的生物学机制和 P4 信号的参与仍不完全清楚。因此，在这里，对黄体晚期和正常黄体溶解时采集的黄体进行了下一代测序（RNA-Seq），并进行了比较。
“黄体退化与黄体溶解的对比”产生了 1595 个差异表达基因（DEG）。黄体晚期退化的 CL 主要与细胞外基质相关的功能术语相关（p=5.52e-05）。其他与转录活性相关的术语（p=2.45e-04）和类固醇激素信号（p=2.29e-04），在黄体晚期退化时比在黄体溶解时更为显著。分娩前的黄体溶解与免疫炎症反应（p=2.87e-14）有关，包括急性期反应（p=4.10e-06）。与正常黄体溶解相比，黄体溶解诱导剂（总共 1480 个 DEG）中的黄体中也有更多的免疫系统相关事件。此外，在妊娠中期撤去 P4 导致 92 个 DEG；在黄体溶解诱导剂处理的犬中，过度表达的术语与炎症反应（p=0.005）或对 IL1 的反应（p=7.29e-05）有关。与增殖相关的术语，例如中心体组织（p=0.002）和类固醇代谢过程（p=0.001），在妊娠中期占主导地位。因此，我们的结果揭示了 P4 在犬黄体中的黄体生成作用的本质。尽管它们导致类固醇生成输出减少，但黄体溶解剂的作用与其在生理分娩时观察到的与 PGF2alpha 相关的炎症反应相比，更多地与 P4 支持的撤回有关。
我们报告了与怀孕和非怀孕犬黄体维持和停止功能相关的差异基因表达。基于差异表达基因，我们指出了潜在参与内分泌和分子机制的功能途径和基因网络。这项研究为未来的研究方向奠定了基础，这些方向可能有助于理解一些临床情况，如黄体功能不足，与犬的不良妊娠结局有关。
