缺失 PRICKLE1 会导致小鼠子宫内膜上皮结构异常、胚胎着床减少和生育能力下降

bioRxiv Pub Date : 2024-08-08 DOI:10.1101/2024.08.06.605120
Emily Roberts, Aishwarya V Bhurke, Sornakala Ganeshkumar, S. Gunewardena, R. Arora, Vargheese M Chennthukuzhi
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引用次数: 0

摘要

胚胎的成功植入需要子宫腔上皮的协调变化,包括结构适应、顶端-基底极性转变、宫腔内液体吸收和细胞通讯。平面细胞极性(PCP)蛋白对细胞组织至关重要,但在子宫生理和着床方面的研究还不够深入。PRICKLE蛋白是PCP的组成成分,被认为在上皮极化和组织形态发生中发挥着关键作用。然而,它们在支持胚胎植入的子宫内膜上皮极化单细胞层中的功能尚不清楚。我们利用 Lactoferrin-iCre 开发了小鼠 Prickle1 的子宫内膜上皮特异性基因敲除(cKO),以研究其在子宫生理中的作用。小鼠子宫内膜上皮的 Prickle1 基因消减会导致胚胎在妊娠 4.5 天前着床减少,从而降低生育能力。子宫的三维成像显示,突变体子宫的管腔折叠异常、管腔闭合受损、腺体长度改变。此外,我们还观察到突变体子宫上皮细胞中的aquaporin-2表达减少、细胞结构紊乱以及E-Cadherin表达和定位改变。在管腔上皮细胞中发现了上皮-间质转化(EMT)的证据,这进一步将 PRICKLE1 的缺失与子宫病变联系在一起。此外,细胞分裂极性的改变导致细胞分裂不完全以及双核或多核细胞的增加,这表明 PRICKLE1 在维持上皮结构方面起着至关重要的作用。我们的研究结果突显了 PRICKLE1 在子宫内 PCP 通路中的关键作用,揭示了它在成功妊娠和生育所必需的分子和细胞反应中的重要性。图形摘要 在小鼠子宫上皮中条件性消减 Prickle1(一个关键的 Wnt/ PCP 基因)会导致细胞分裂平面改变和细胞分裂不完全,从而导致双核/多核细胞、上皮-间质转化、腺体长度改变和植入缺陷。部分图片改编自 BioRender.com(2024 年)。意义声明 保守的细胞分裂对维持子宫顶端-基底极性和上皮的正常功能至关重要。据推测,Wnt/平面细胞极性信号分子可提供空间线索,使单细胞、二维片状上皮细胞在与顶端-基底极性正交的平面上组织起来。在小鼠子宫上皮中条件性消减 Prickle1(一个关键的 Wnt/ PCP 基因)会导致上皮粘连蛋白表达异常、细胞分裂平面改变、细胞分裂不完全导致双核/多核细胞、上皮-间质转化和植入缺陷。Prickle1 在维持对称子宫上皮细胞分裂和组织结构方面的作用在 Wnt/PCP 基因(包括之前描述的 Vangl2、Ror2 和 Wnt5a 小鼠模型)中是独一无二的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Loss of PRICKLE1 leads to abnormal endometrial epithelial architecture, decreased embryo implantation, and reduced fertility in mice
Successful embryo implantation requires coordinated changes in the uterine luminal epithelium, including structural adaptations, apical-basal polarity shifts, intrauterine fluid resorption, and cellular communication. Planar cell polarity (PCP) proteins, essential for cell organization, are understudied in the context of uterine physiology and implantation. PRICKLE proteins, components of PCP, are suggested to play critical roles in epithelial polarization and tissue morphogenesis. However, their function in the polarized unicellular layer of endometrial epithelium, which supports embryo implantation, is unknown. We developed an endometrial epithelial-specific knockout (cKO) of mouse Prickle1 using Lactoferrin-iCre to investigate its’s role in uterine physiology. Prickle1 ablation in the endometrial epithelium of mice resulted in decreased embryo implantation by gestational day 4.5 leading to lower fertility. Three-dimensional imaging of the uterus revealed abnormal luminal folding, impaired luminal closure, and altered glandular length in mutant uteri. Additionally, we observed decreased aquaporin-2 expression, disrupted cellular architecture, and altered E-Cadherin expression and localization in the mutant uterine epithelium. Evidence of epithelial-mesenchymal transition (EMT) was found within luminal epithelial cells, further linking PRICKLE1 loss to uterine pathologies. Furthermore, altered polarity of cell division leading to incomplete cytokinesis and increase in binuclear or multinucleated cells suggests a crucial role for PRICKLE1 in the maintenance of epithelial architecture. Our findings highlight PRICKLE1’s critical role in the PCP pathway within the uterus, revealing its importance in the molecular and cellular responses essential for successful pregnancy and fertility. Graphical Abstract Conditional ablation of Prickle1, a crucial Wnt/ PCP gene, in mouse uterine epithelium results in altered plane of cell division and incomplete cytokinesis leading to binucleated/multinucleated cells, epithelial – mesenchymal transition, altered gland length, and defective implantation. Some images adapted from BioRender.com (2024). Significance Statement Conservative cell division is essential to maintain apical-basal polarity and proper epithelial function in the uterus. Wnt/ Planar cell polarity signaling molecules are hypothesized to provide the spatial cues to organize unicellular, 2-dimensional sheet of epithelium in a plane orthogonal to the apical-basal polarity. Conditional ablation of Prickle1, a crucial Wnt/ PCP gene, in mouse uterine epithelium results in aberrant expression of epithelial cadherin, altered plane of cell division, incomplete cytokinesis leading to binucleated/ multinucleated cells, epithelial – mesenchymal transition, and defective implantation. Role of Prickle1 in maintaining symmetric uterine epithelial cell division and tissue architecture is unique among Wnt/PCP genes, including previously described mouse models for Vangl2, Ror2, and Wnt5a.
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