Impaired distribution of retinoic acid receptors in the hindgut-tailgut region of murine embryos with anorectal malformations
Impaired distribution of retinoic acid receptors in the hindgut-tailgut region of murine embryos with anorectal malformations
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DOI：
10.1053/jpsu.2001.20721
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发表时间：
2001-02-01
影响因子：
2.4
通讯作者：
Iwai, N
中科院分区：
文献类型：
--
作者：
Bitoh, Y;Shimotake, T;Iwai, N
背景/目的：类维生素A介导的信号转导在各种器官的器官发生中起着至关重要的作用。为了探讨肛门直肠畸形（ARM）的发病机制，作者研究了过量全反式视黄酸（ATRA）诱导的ARM小鼠胚胎中视黄酸受体（RAR）的分布模式。方法：在妊娠第九天（E9.0）对妊娠小鼠灌胃100 mg/kg的ATRA。在E11.0和E14.0之间获得胚胎并立即固定在4%多聚甲醛溶液中。使用专门针对 RAR-α、RAR-β 和 RAR-gamma 产生的抗体制备冰冻切片进行免疫组织化学分析。结果：接受 ATRA 治疗的胚胎中，超过 98% 具有 ARM；直肠前列腺尿道和直肠泄殖腔瘘是最常见的异常情况。在E11.5的正常胚胎的后肠-尾肠上皮中同样发现了RAR-α的免疫反应性。然而，在处理的胚胎中后肠中不存在它，RAR-β和RAR-γ的免疫反应性在远端后肠中没有显示出差异。结论：E11.5时RAR-α在后肠尾部的分布受损导致E14.0时泄殖腔和直肠尿道或直肠泄殖腔瘘的不完全分隔。这些结果表明，过量的 ATRA 通过直接破坏类维生素A介导的信号通路来影响远端后肠发育。版权所有 (C) 2001 W.B.桑德斯公司。
Background/Purpose: Retinoid-mediated signal transduction plays a crucial role in the organogenesis of various organs. To investigate the pathogenesis of anorectal malformations (ARM), the authors studied the distribution pattern of retinoic acid receptors (RARs) in ARM murine embryos induced by overdose of all-trans retinoic acid (ATRA).Methods: Pregnant mice were gavage-fed 100 mg/kg of ATRA on the ninth gestational day (E9.0). Embryos were obtained between E11.0 and E14.0 and were fixed immediately in a 4% paraformaldehyde solution. Frozen sections were prepared for immunohistochemistry using antibodies specifically raised against RAR-alpha, RAR-beta, and RAR-gamma.Results: Over 98% of the embryos administered ATRA had ARM; rectoprostatic urethral and rectocloacal fistulas were the most frequent anomalies. The immunoreactivity of RAR-alpha was found equally in the epithelium of hindgut-tailgut in normal embryos on E11.5. However, it was absent in the hindgut in the treated embryos, The immunoreactivities of RAR-beta and RAR-gamma showed no difference in the distal hindgut.Conclusions: Impaired distribution of RAR-alpha in the hindgut-tailglut on E11.5 resulted in the incomplete partitioning of the cloaca and the rectourethral or rectocloacal fistula on E14.0. These results suggest that overdose of ATRA affects the distal hindgut development by directly disrupting the retinoid-mediated signalling pathway. Copyright (C) 2001 by W.B. Saunders Company.