SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease.
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.
['Tang|Weibing|W|', 'Tang|Junwei|J|', 'He|Jun|J|', 'Zhou|Zhigang|Z|', 'Qin|Yufeng|Y|', 'Qin|Jingjing|J|', 'Li|Bo|B|', 'Xu|Xiaoqun|X|', 'Geng|Qiming|Q|', 'Jiang|Weiwei|W|', 'Wu|Wei|W|', 'Wang|Xinru|X|', 'Xia|Yankai|Y|']
D000818:Animals D015153:Blotting, Western D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D003106:Colon D004268:DNA-Binding Proteins D005260:Female D015870:Gene Expression D006627:Hirschsprung Disease D006801:Humans D007223:Infant D036341:Intercellular Signaling Peptides and Proteins D008297:Male D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D035683:MicroRNAs D009419:Nerve Tissue Proteins D011485:Protein Binding D051096:Proto-Oncogene Proteins c-ret D011971:Receptors, Immunologic D020133:Reverse Transcriptase Polymerase Chain Reaction D015398:Signal Transduction
gene regulation genetic disorder intestine neural development