PDF(Pubmed)
Abstract：
Anorectal malformations (ARMs) are congenital diseases that lead to postoperative fecal incontinence, constipation, and soiling, despite improvements in surgery; however, their pathological mechanisms remain unclear. Here, we report the role of microRNA-141-3p in maintaining homeostasis between apoptosis and autophagy in the lumbosacral defecation center of fetal rats with ARMs. Elevated microRNA-141-3p expression inhibited YIN-YANG-1 expression by binding its 3\' UTR, and repressed autophagy and triggered apoptosis simultaneously. Then, adenylate cyclase 3 was screened to be the downstream target gene of YIN-YANG-1 by chromatin immunoprecipitation sequencing experiments, and Yin Yang 1 could positively activate the transcription of adenylate cyclase 3 by directly interacting with the motif GAGATGG and ATGG in its promoter. Intraamniotic microinjection of adeno-rno-microRNA-141-3p-sponge-GFP in fetal rats with ARMs on embryonic day 15 restored apoptosis-autophagy homeostasis. These findings reveal that microRNA-141-3p upregulation impaired homeostasis between apoptosis and autophagy by inhibiting the YIN-YANG-1/adenylate cyclase 3 axis, and that intraamniotic injection of anti-microRNA-141-3p helped maintain homeostasis in the lumbosacral defecation center of ARMs during embryogenesis.
摘要：
肛门直肠畸形（ARM）是导致术后大便失禁的先天性疾病，便秘,弄脏，尽管手术有所改善；然而，其病理机制尚不清楚。这里,我们报道了microRNA-141-3p在维持胚胎大鼠腰骶部排便中心细胞凋亡和自噬之间的稳态中的作用。升高的microRNA-141-3p表达通过结合其3'UTR抑制YIN-YANG-1表达，抑制自噬并同时触发细胞凋亡。然后，通过染色质免疫沉淀测序实验,筛选出腺苷酸环化酶3为YIN-YANG-1的下游靶基因,阴阳1可以通过与启动子中的基序GAGATGG和ATGG直接相互作用来正向激活腺苷酸环化酶3的转录。在胚胎第15天，羊膜内微量注射adeno-rno-microRNA-141-3p-海绵-GFP在具有ARM的胎儿大鼠中恢复了凋亡-自噬稳态。这些发现揭示了microRNA-141-3p上调通过抑制YIN-YANG-1/腺苷酸环化酶3轴损害细胞凋亡和自噬之间的稳态,羊膜腔内注射抗microRNA-141-3p有助于维持胚胎发育过程中ARM腰骶排便中心的稳态。
