LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice.
LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice.
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DOI：
10.1053/j.gastro.2015.04.018
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发表时间：
2015-08
期刊：
影响因子：
29.4
通讯作者：
Coffey RJ
中科院分区：
文献类型：
--
作者：
Kondo J;Powell AE;Wang Y;Musser MA;Southard-Smith EM;Franklin JL;Coffey RJ
Cajal间质细胞（Interstitial cells of Cajal，ICC）通过控制肠平滑肌收缩来调节肠道运动。肌间神经丛平面内的ICC（ICC-MY）在小鼠胚胎发生期间由c-Kit阳性祖细胞产生。然而，对小肠深肌丛相关ICC和结肠粘膜下神经丛相关ICC的个体发生知之甚少。富含亮氨酸的重复序列和免疫球蛋白样结构域蛋白1（LRIG 1）标志着肠上皮干细胞，但LRIG 1在非上皮肠细胞中的作用尚未确定。我们试图确定ICC-BMPs和ICC-SMP的个体发育，以及LRIG 1是否在它们的发育中起作用。通过免疫荧光和转运试验分析LRIG 1缺失小鼠（纯合Lrig 1-CreERT 2）和野生型小鼠。通过口服罗丹明B-结合葡聚糖的通道评价转运。将Lrig 1-CreERT 2小鼠或具有在诱导型平滑肌启动子控制下的CreERT 2的小鼠（Myh 11-CreERT 2）与Rosa 26-LSL-YFP小鼠杂交以进行谱系追踪分析。在免疫荧光测定中，发现ICC-CMC和ICC-SMP表达LRIG 1。基于谱系追踪，ICC-BMP和ICC-SMP各自产生于LRIG 1阳性平滑肌祖细胞。在LRIG 1基因敲除小鼠中，c-Kit和SMP区域以及2种额外ICC标志物（ANO 1和NK 1 R）的染色丢失。与对照小鼠相比，LRIG 1基因敲除小鼠的小肠转运显著延迟。LRIG 1调节小鼠平滑肌祖细胞的ICC-BMP和ICC-SMP的出生后发育在LRIG 1-null小鼠中观察到的小肠转运减慢可能至少部分是由于ICC-ESTs群体的损失。
Interstitial cells of Cajal (ICC) control intestinal smooth muscle contraction to regulate gut motility. ICC within the plane of the myenteric plexus (ICC-MY) arise from c-Kit-positive progenitor cells during mouse embryogenesis. However, little is known about the ontogeny of ICC associated with the deep muscle plexus (ICC-DMP) in the small intestine and ICC associated with the submucosal plexus (ICC-SMP) in the colon. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) marks intestinal epithelial stem cells, but the role of LRIG1 in non-epithelial intestinal cells has not been identified. We sought to determine the ontogeny of ICC-DMP and ICC-SMP, and whether LRIG1 has a role in their development. LRIG1-null mice (homozygous Lrig1-CreERT2) and wild-type mice were analyzed by immunofluorescence and transit assays. Transit was evaluated by passage of orally administered rhodamine B-conjugated dextran. Lrig1-CreERT2 mice or mice with CreERT2 under control of an inducible smooth muscle promoter (Myh11-CreERT2) were crossed with Rosa26-LSL-YFP mice for lineage tracing analysis. In immunofluorescence assays, ICC-DMP and ICC-SMP were found to express LRIG1. Based on lineage tracing, ICC-DMP and ICC-SMP each arose from LRIG1-positive smooth muscle progenitors. In LRIG1-null mice, there was loss of staining for c-Kit in DMP and SMP regions, as well as for 2 additional ICC markers (ANO1 and NK1R). LRIG1-null mice had significant delays in small intestinal transit, compared with control mice. LRIG1 regulates the post-natal development of ICC-DMP and ICC-SMP from smooth muscle progenitors in mice. Slowed small intestinal transit observed in LRIG1-null mice may be due, at least in part, to loss of the ICC-DMP population.