Kit signaling is essential for development and maintenance of interstitial cells of Cajal and electrical rhythmicity in the embryonic gastrointestinal tract
Kit signaling is essential for development and maintenance of interstitial cells of Cajal and electrical rhythmicity in the embryonic gastrointestinal tract
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DOI：
10.1002/dvdy.20929
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发表时间：
2007-01-01
影响因子：
2.5
通讯作者：
Ward, Sean M.
中科院分区：
文献类型：
--
作者：
Beckett, Elizabeth A. H.;Ro, Seungil;Ward, Sean M.
卡哈尔间质细胞（ICC）是平滑肌器官中的特化细胞，产生和传播起搏活动，接收来自运动神经元的输入，并充当机械传感器。在胃肠道中，ICC表型的发育和维持与通过Kit的细胞内信号传导有关，但其在胚胎发生期间ICC发育中的作用存在争议。在这里，我们研究了小鼠妊娠晚期功能性ICC-MY的发育。在自发性电活动（E17至P0）发生前后使用中和抗体阻断Kit导致ICC-MY网络和起搏器活性丧失。ICC-MY和起搏活性在W/+和W-V/+杂合子中正常发育，但在Kit功能受损的W/W-V胚胎中，在E17至PO之间未能发育。从E17-P0开始，用Kit中和抗体或酪氨酸激酶抑制剂甲磺酸伊马替尼（STI 571）处理肌肉3天，导致功能发育的ICC-MY网络丧失，但ICC-MY和起搏器活性在停止中和抗体或甲磺酸伊马替尼治疗后9天内恢复。这些数据表明，Kit信号是一个重要的因素，在血统的决定和功能性ICC在妊娠晚期的发展。ICC-MY在胃肠道组织中表现出显著的可塑性。ICC表型的操作可能提供有用的治疗在胃肠道疾病中的试剂盒阳性细胞群丢失或扩增。
Interstitial cells of Cajal (ICC) are specialized cells in smooth muscle organs that generate and propagate pacemaker activity, receive inputs from motor neurons, and serve as mechanosensors. In the gastrointestinal tract, development and maintenance of the ICC phenotype have been linked to intracellular signaling via Kit, but its role in development of ICC during embryogenesis is controversial. Here we have studied the development of functional ICC-MY during the late gestational period in mice. Blocking Kit with a neutralizing antibody before and after development of spontaneous electrical activity (E17 to P0) caused loss of ICC-MY networks and pacemaker activity. ICC-MY and pacemaker activity developed normally in W/+ and W-V/+ heterozygotes, but failed to develop between E17 to PO in W/W-V embryos with compromised Kit function. Muscles treated with Kit neutralizing antibody or the tyrosine kinase inhibitor, imatinib mesylate (STI571), from E17-P0 for 3 days caused loss of functionally developed ICC-MY networks, but ICC-MY and pacemaker activity recovered within 9 days after discontinuing treatment with neutralizing antibody or imatinib mesylate. These data suggest that Kit signaling is an important factor in lineage decision and in the development of functional ICC in late gestation. ICC-MY demonstrate significant plasticity in gastrointestinal tissues. Manipulation of the ICC phenotype might provide useful therapies in gastrointestinal disease where the Kit-positive cell population is either lost or amplified.