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LGR4基因敲除小鼠雄性生殖道的产后发育缺陷

Defective postnatal development of the male reproductive tract in LGR4 knockout mice.

作者信息

Mendive Fernando, Laurent Patrick, Van Schoore Grégory, Skarnes William, Pochet Roland, Vassart Gilbert

机构信息

Institut de Recherche en Biologie Humaine et Moléculaire (IRIBHM), University of Brussels (ULB), Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium.

出版信息

Dev Biol. 2006 Feb 15;290(2):421-34. doi: 10.1016/j.ydbio.2005.11.043. Epub 2006 Jan 9.

Abstract

The final outcome of tube elongation and branching is to maximize the epithelial exchange surfaces in tubular organs. The molecular and cellular basis of these processes is actively studied in model organs such as mammary glands, liver and kidney, but they remain almost unexplored in the male reproductive tract. Here, we report that the orphan G protein-coupled receptor LGR4/GPR48 plays a role in the postnatal tissue remodeling needed for elongation and convolution of the efferent ducts and epididymis. In LGR4 knockout male mice, tube elongation fails, resulting in a hypoplastic and poorly convoluted tract. Cell proliferation is dramatically reduced in KO affected tissues, providing an explanation to the observed phenotype. Detailed analysis showed that LGR4 inactivation manifests differently in the affected organs. In efferent ducts, immune cells infiltrate the epithelium and reach the lumen, blocking the transit of sperm and testicular fluid. In addition, the hypoplasia and low convolution result in a reduction of the epithelial area involved in liquid reabsorption. Both phenomena contribute in tissue swelling upstream the blockade due to liquid and sperm accumulation, with secondary damaging effects on the germinal epithelium. In the epididymis, the thin and highly convoluted duct is replaced by a large cystic tube which is surrounded by a thick condensation of mesenchymal cells. The abnormal organization of the cellular compartments in and around the ducts suggests that LGR4 might play a role in epithelial-mesenchymal interactions. Altogether, our data identify LGR4 as an important signaling molecule implicated in the tube morphogenesis of the male reproductive tract.

摘要

管道延长和分支的最终结果是使管状器官中的上皮交换表面最大化。在诸如乳腺、肝脏和肾脏等模型器官中,人们积极研究这些过程的分子和细胞基础,但在男性生殖道中它们几乎仍未被探索。在此,我们报告孤儿G蛋白偶联受体LGR4/GPR48在出生后输出小管和附睾延长及卷曲所需的组织重塑中发挥作用。在LGR4基因敲除的雄性小鼠中,管道延长失败,导致发育不全且卷曲不良的管道系统。在基因敲除影响的组织中细胞增殖显著减少,这为所观察到的表型提供了解释。详细分析表明,LGR4失活在受影响的器官中表现不同。在输出小管中,免疫细胞浸润上皮并到达管腔,阻断精子和睾丸液的运输。此外,发育不全和低卷曲导致参与液体重吸收的上皮面积减少。这两种现象都导致由于液体和精子积聚而在阻塞上游的组织肿胀,对生精上皮产生继发性损伤作用。在附睾中,细且高度卷曲的管道被一个大的囊性管取代,该囊性管被间充质细胞的厚凝聚物包围。管道内外细胞区室的异常组织表明LGR4可能在上皮-间充质相互作用中发挥作用。总之,我们的数据确定LGR4是参与男性生殖道管道形态发生的重要信号分子。

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