Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice
Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice
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DOI：
10.1016/j.ydbio.2014.03.009
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发表时间：
2014-06-15
影响因子：
2.7
通讯作者：
Tchorz, Jan S.
中科院分区：
文献类型：
--
作者：
Kinzel, Bernd;Pikiolek, Monika;Tchorz, Jan S.
Lgr4和Lgr5是各种器官中成体和胚胎组织干细胞的已知标记。然而，Lgr4 和 Lgr5 对于胚胎发育是否重要仍不清楚。为了研究它们在肠隐窝、皮肤和肾脏发育过程中的功能，我们现在培养了缺乏 Lgr4 (Lgr4KO)、Lgr5 (Lgr5KO) 或两种受体 (Lgr4/5dKO) 的小鼠。 E16.5 Lgr4KO 小鼠表现出 Lgr5+/Olfm4+ 肠干细胞完全丧失、Wnt 信号传导受损以及肠上皮增殖和分化受损。同样，E16.5 Lgr4KO 小鼠表现出发育中皮肤的基底细胞增殖和毛囊数量减少，以及肾小管扩张和鲍曼间隙扩张。尽管Lgr4KO和Lgr5KO小鼠均在围产期死亡，但Lgr5缺失并没有损害肠道、肾脏或皮肤的胚胎发育。 Lgr4 和 Lgr5 的同时删除并不能阻止围产期致死率，与之前的报告相反，该报告建议通过低等态 Lgr4 突变体来挽救 Lgr5 KO 围产期致死率。虽然双重缺失并没有进一步促进在 Lgr4KO 肠道中观察到的表型，但仅在 Lgr4/5dKO 小鼠中观察到肾细胞增殖受损、表皮厚度减少、Lgr5+ 毛囊上皮损失和毛囊发育受损。这支持两种受体的互补功能。我们的研究结果清楚地证实了 Lgr4 和 Lgr5 在胚胎肠道、皮肤和肾脏发育过程中的重要性，其中 Lgr4 起主导作用。 (C) 2014 Elsevier Inc. 保留所有权利。
Lgr4 and Lgr5 are known markers of adult and embryonic tissue stem cells in various organs. However, whether Lgr4 and Lgr5 are important for embryonic development remains unclear. To study their functions during intestinal crypt, skin and kidney development we now generated mice lacking either Lgr4 (Lgr4KO), Lgr5 (Lgr5KO) or both receptors (Lgr4/5dKO). E16.5 Lgr4KO mice displayed complete loss of Lgr5+/Olfm4+intestinal stem cells, compromised Wnt signaling and impaired proliferation and differentiation of gut epithelium. Similarly, E16.5 Lgr4KO mice showed reduced basal cell proliferation and hair follicle numbers in the developing skin, as well as dilated kidney tubules and ectatic Bowman's spaces. Although Lgr4KO and Lgr5KO mice both died perinatally, Lgr5 deletion did not compromise embryonic development of gut, kidney or skin. Concomitant deletion of Lgr4 and Lgr5 did not prevent perinatal lethality, in contrast to a previous report that suggested rescue of Lgr5 KO perinatal lethality by a hypomorphic Lgr4 mutant. While the double deletion did not further promote the phenotypes observed in Lgr4KO intestines, impaired kidney cell proliferation, reduced epidermal thickness, loss of Lgr5+follicular epithelium and impaired hair follicle development were only observed in Lgr4/5dKO mice. This supports complementary functions of both receptors. Our findings clearly establish the importance of Lgr4 and Lgr5 during embryonic gut, skin and kidney development, with a dominant role of Lgr4. (C) 2014 Elsevier Inc. All rights reserved.