Roberts Emily R, Bhurke Aishwarya V, Ganeshkumar Sornakala, Gunewardena Sumedha, Arora Ripla, Chennthukuzhi Vargheese M
bioRxiv. 2024 Aug 20:2024.08.06.605120. doi: 10.1101/2024.08.06.605120.
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 using to investigate its's role in uterine physiology. 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.
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 , 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 in maintaining symmetric uterine epithelial cell division and tissue architecture is unique among Wnt/PCP genes, including previously described mouse models for and . Biological Sciences (Major) Cell Biology (Minor), Physiology (Minor).
成功的胚胎着床需要子宫腔上皮发生协调变化，包括结构适应、顶-基极性转变、子宫内液体重吸收和细胞通讯。平面细胞极性（PCP）蛋白对细胞组织至关重要，但在子宫生理学和着床背景下研究较少。PRICKLE蛋白是PCP的组成部分，被认为在上皮极化和组织形态发生中起关键作用。然而，它们在支持胚胎着床的子宫内膜上皮单细胞极化层中的功能尚不清楚。我们利用[具体技术]构建了小鼠子宫内膜上皮特异性敲除（cKO）模型，以研究其在子宫生理学中的作用。小鼠子宫内膜上皮中的[基因名称]缺失导致到妊娠第4.5天时胚胎着床减少，生育力降低。子宫的三维成像显示，突变子宫的腔折叠异常、腔闭合受损和腺体长度改变。此外，我们观察到突变子宫上皮中aquaporin-2表达降低、细胞结构破坏以及E-钙黏蛋白表达和定位改变。在腔上皮细胞内发现了上皮-间质转化（EMT）的证据，进一步将PRICKLE1缺失与子宫病变联系起来。此外，细胞分裂极性改变导致胞质分裂不完全以及双核或多核细胞增加，表明PRICKLE1在维持上皮结构中起关键作用。我们的研究结果突出了PRICKLE1在子宫内PCP途径中的关键作用，揭示了其在成功妊娠和生育所必需的分子和细胞反应中的重要性。
保守的细胞分裂对于维持子宫内的顶-基极性和适当的上皮功能至关重要。Wnt/平面细胞极性信号分子被假设为提供空间线索，以在与顶-基极性正交的平面中组织单细胞二维上皮片层。在小鼠子宫上皮中条件性敲除关键的Wnt/PCP基因[基因名称]会导致上皮钙黏蛋白异常表达、细胞分裂平面改变、胞质分裂不完全导致双核/多核细胞、上皮-间质转化以及着床缺陷。在维持对称的子宫上皮细胞分裂和组织结构方面，[基因名称]的作用在Wnt/PCP基因中是独特的，包括先前描述的[相关基因]小鼠模型。生物学（主修）细胞生物学（辅修），生理学（辅修）。
