Anderson Richard B, Turner Kirsty N, Nikonenko Alexander G, Hemperly John, Schachner Melitta, Young Heather M
Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Australia.
Gastroenterology. 2006 Apr;130(4):1221-32. doi: 10.1053/j.gastro.2006.01.002.
BACKGROUND & AIMS: During development, the enteric nervous system is derived from neural crest cells that emigrate from the hindbrain, enter the foregut, and colonize the gut. Defects in neural crest migration can result in intestinal aganglionosis. Hirschsprung's disease (congenital aganglionosis) is a human condition in which enteric neurons are absent from the distal bowel. A number of clinical studies have implicated the cell adhesion molecule L1 in Hirschsprung's disease. We examined the role of L1 in the migration of neural crest cells through the developing mouse gut.
A variety of in vitro and in vivo assays were used to examine: (1) the effect of L1 blocking antibodies or exogenous soluble L1 protein known to compromise L1 function on the rate of crest cell migration, (2) the effect of blocking L1 activity on the dynamic behavior of crest cells using time-lapse microscopy, and (3) whether the colonization of the gut by crest cells in L1-deficient mice differs from control mice.
We show that L1 is expressed by neural crest cells as they colonize the gut. Perturbation studies show that disrupting L1 activity retards neural crest migration and increases the number of solitary neural crest cells. L1-deficient mice show a small but significant reduction in neural crest cell migration at early developmental stages, but the entire gastrointestinal tract is colonized.
L1 is important for the migration of neural crest cells through the developing gut and is likely to be involved in the etiology of Hirschsprung's disease.
在发育过程中，肠神经系统源自神经嵴细胞，这些细胞从后脑迁移出来，进入前肠，并在肠道中定植。神经嵴迁移缺陷可导致肠道神经节细胞缺失。先天性巨结肠症（先天性神经节细胞缺失症）是一种人类疾病，其远端肠道中缺乏肠神经元。多项临床研究表明细胞黏附分子L1与先天性巨结肠症有关。我们研究了L1在神经嵴细胞通过发育中的小鼠肠道迁移过程中的作用。
使用多种体外和体内试验来检测：（1）已知会损害L1功能的L1阻断抗体或外源性可溶性L1蛋白对嵴细胞迁移速率的影响；（2）使用延时显微镜观察阻断L1活性对嵴细胞动态行为的影响；（3）L1缺陷小鼠中嵴细胞在肠道中的定植情况与对照小鼠是否不同。
我们发现神经嵴细胞在定植于肠道时表达L1。干扰研究表明，破坏L1活性会延迟神经嵴迁移并增加单个神经嵴细胞的数量。L1缺陷小鼠在早期发育阶段神经嵴细胞迁移有轻微但显著的减少，但整个胃肠道仍被定植。
L1对神经嵴细胞通过发育中的肠道迁移很重要，并且可能参与先天性巨结肠症的病因学。
