title: SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease.
abstract: Hirschsprung's disease (HSCR) is a rare congenital disease caused by impaired proliferation and migration of neural crest cells. We investigated changes in expression of microRNAs (miRNAs) and the genes they regulate in tissues of patients with HSCR. Quantitative real-time PCR and immunoblot analyses were used to measure levels of miRNA, mRNAs, and proteins in colon tissues from 69 patients with HSCR and 49 individuals without HSCR (controls). Direct interactions between miRNAs and specific mRNAs were indentified in vitro, while the function role of miR-218-1 was investigated by using miR-218 transgenic mice. An increased level of miR-218-1 correlated with increased levels of SLIT2 and decreased levels of RET and PLAG1 mRNA and protein. The reductions in RET and PLAG1 by miR-218-1 reduced proliferation and migration of SH-SY5Y cells. Overexpression of the secreted form of SLIT2 inhibited cell migration via binding to its receptor ROBO1. Bowel tissues from miR-218-1 transgenic mice had nerve fibre hyperplasia and reduced numbers of gangliocytes, compared with wild-type mice. Altered miR-218-1 regulation of SLIT2, RET and PLAG1 might be involved in the pathogenesis of HSCR.
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China.
authors: Weibing
authors: W
authors: Tang
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China.
authors: Junwei
authors: J
authors: Tang
authors: Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Jun
authors: J
authors: He
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China.
authors: Zhigang
authors: Z
authors: Zhou
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.
authors: Yufeng
authors: Y
authors: Qin
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China.
authors: Jingjing
authors: J
authors: Qin
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China.
authors: Bo
authors: B
authors: Li
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China.
authors: Xiaoqun
authors: X
authors: Xu
authors: Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China.
authors: Qiming
authors: Q
authors: Geng
authors: Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China.
authors: Weiwei
authors: W
authors: Jiang
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.
authors: Wei
authors: W
authors: Wu
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.
authors: Xinru
authors: X
authors: Wang
authors: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.
authors: Yankai
authors: Y
authors: Xia
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006627:Hirschsprung Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D051096:Proto-Oncogene Proteins c-ret; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C547471:MIRN218 microRNA, human; C104382:PLAG1 protein, human; C099282:RET protein, human
keywords: gene regulation; genetic disorder; intestine; neural development