Embryonic Lethality Due to Arrested Cardiac Development in Psip1/Hdgfrp2 Double-Deficient Mice.
Embryonic Lethality Due to Arrested Cardiac Development in Psip1/Hdgfrp2 Double-Deficient Mice.
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DOI：
10.1371/journal.pone.0137797
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Engelman AN
中科院分区：
文献类型：
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作者：
Wang H;Shun MC;Dickson AK;Engelman AN
肝细胞瘤衍生生长因子 (HDGF) 相关蛋白 2 (HRP2) 和晶状体上皮衍生生长因子 (LEDGF)/p75 是 HRP2 蛋白家族密切相关的成员。 LEDGF/p75 与许多人类病理学有关，包括癌症、自身免疫和传染病。此前研究表明，敲除编码 LEDGF/p75 和较短的 LEDGF/p52 亚型的 Psip1 基因会导致小鼠围产期死亡。相比之下，HRP2 的功能很大程度上是未知的。为了了解 HRP2 在发育中的作用，我们在正常小鼠和 Psip1 敲除小鼠中敲除了编码 HRP2 的 Hdgfrp2 基因。 Hdgfrp2 敲除小鼠发育正常并且具有生育能力。相比之下，双缺陷小鼠大约在胚胎第 (E) 13.5 天死亡。组织学检查显示室间隔缺损 (VSD) 与 E14.5 双敲除胚胎相关。为了研究潜在的分子机制，在 Illumina 平台上对从心室组织中回收的 RNA 进行 RNA 测序。生物信息学分析揭示了一些基因和生物途径因 Psip1 敲除和/或 Psip1/Hdgfrp2 双敲除而显着失调。在已知编码 LEDGF/p75 结合因子的十几个基因中，只有编码 RNA 剪接因子的 Nova1 的表达因敲除而显着失调。然而，其他 RNA 剪接因子（包括 LEDGF/p52 相互作用蛋白 ASF/SF2）的表达没有显着改变，表明整体 RNA 剪接的失调并不是 VSD 病理学的驱动因素。肿瘤生长因子 (Tgf) β-信号传导在发育过程中的心脏形态发生中发挥关键作用，与对照和 Psip1 敲除样本相比，它是双敲除显着失调的唯一途径。因此，我们推测 Tgf-β 信号失调是导致 Psip1/Hdgfrp2 双缺陷小鼠发生 VSD 和产前致死的一个因素。
Hepatoma-derived growth factor (HDGF) related protein 2 (HRP2) and lens epithelium-derived growth factor (LEDGF)/p75 are closely related members of the HRP2 protein family. LEDGF/p75 has been implicated in numerous human pathologies including cancer, autoimmunity, and infectious disease. Knockout of the Psip1 gene, which encodes for LEDGF/p75 and the shorter LEDGF/p52 isoform, was previously shown to cause perinatal lethality in mice. The function of HRP2 was by contrast largely unknown. To learn about the role of HRP2 in development, we knocked out the Hdgfrp2 gene, which encodes for HRP2, in both normal and Psip1 knockout mice. Hdgfrp2 knockout mice developed normally and were fertile. By contrast, the double deficient mice died at approximate embryonic day (E) 13.5. Histological examination revealed ventricular septal defect (VSD) associated with E14.5 double knockout embryos. To investigate the underlying molecular mechanism(s), RNA recovered from ventricular tissue was subjected to RNA-sequencing on the Illumina platform. Bioinformatic analysis revealed several genes and biological pathways that were significantly deregulated by the Psip1 knockout and/or Psip1/Hdgfrp2 double knockout. Among the dozen genes known to encode for LEDGF/p75 binding factors, only the expression of Nova1, which encodes an RNA splicing factor, was significantly deregulated by the knockouts. However the expression of other RNA splicing factors, including the LEDGF/p52-interacting protein ASF/SF2, was not significantly altered, indicating that deregulation of global RNA splicing was not a driving factor in the pathology of the VSD. Tumor growth factor (Tgf) β-signaling, which plays a key role in cardiac morphogenesis during development, was the only pathway significantly deregulated by the double knockout as compared to control and Psip1 knockout samples. We accordingly speculate that deregulated Tgf-β signaling was a contributing factor to the VSD and prenatal lethality of Psip1/Hdgfrp2 double-deficient mice.