Gershon M D, Tennyson V M
Department of Anatomy and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, NY 10032.
Prog Clin Biol Res. 1991;373:257-76.
In order to gain insight into the molecular nature of some of the interactions that shape the ontogeny of the ENS, we have been studying two murine models in which enteric neural development is abnormal. One is the lethal spotted (ls/ls) mutant mouse. The other is a line of transgenic mice ("1975-2") that overexpress a homeobox-containing gene, Hox-1.4. Megacolon, an expansion of the bowel proximal to an abnormally innervated terminal gut, develops in each of these mice; however, the animals differ with respect to the nature of their neural defect. In ls/ls mice the terminal bowel is congenitally aganglionic (although hyperinnervated with nerve processes), because it cannot be colonized by migrating crest-derived cells. In contrast, the terminal gut of the transgenic (1975-2) mice contains ganglia, but the ultrastructure of these ganglia is that of peripheral, not enteric, nerve. On the basis of observations made thus far, we postulate that the ls/ls defect arises as a result of an overabundance and maldistribution of molecular components of basal laminae (such as laminin), which we have observed in the presumptive aganglionic bowel. We propose that crest-derived cells acquire a nerve-related laminin receptor when they enter the gut, which, when activated, induces these cells to withdraw from the cell cycle, differentiate, and extend neurites (or glial processes). Excessive laminin causes this response to occur prematurely. Cells that differentiate into neurons or glia presumably no longer migrate; therefore, the bowel distal to the region in which they respond to the abnormal extracellular ls/ls matrix does not become colonized by crest-derived cells. The molecular defect in the 1975-2 animals is unknown, but it would appear that it interferes, not with the migration of crest-derived cells, but with their subsequent differentiation along lineages appropriate to the bowel. Since the Hox-1.4 gene is overexpressed throughout the length of the gut, and not just in the abnormal section, we propose that prolonged exposure of neural precursors to cells that overexpress the Hox-1.4 gene product, renders the neural precursors unresponsive to the effects of the enteric microenvironment on neural differentiation. The abnormal zone of the 1975-2 bowel, therefore, is the region last to be colonized by crest-derived cells.
为了深入了解一些影响肠神经系统个体发育的相互作用的分子本质，我们一直在研究两种肠神经发育异常的小鼠模型。一种是致死斑点（ls/ls）突变小鼠。另一种是过表达含同源框基因Hox-1.4的转基因小鼠品系（“1975-2”）。在这些小鼠中均会出现巨结肠，即异常神经支配的终末肠近端的肠管扩张；然而，这些动物在神经缺陷的本质方面存在差异。在ls/ls小鼠中，终末肠先天性无神经节（尽管有神经突起过度支配），因为它不能被迁移的神经嵴衍生细胞定植。相比之下，转基因（1975-2）小鼠的终末肠含有神经节，但这些神经节的超微结构是外周神经而非肠神经的超微结构。基于目前的观察结果，我们推测ls/ls缺陷是由于基膜分子成分（如层粘连蛋白）过多和分布异常所致，我们在假定的无神经节肠中观察到了这种情况。我们提出，神经嵴衍生细胞进入肠道时会获得一种与神经相关的层粘连蛋白受体，该受体被激活时会诱导这些细胞退出细胞周期、分化并延伸神经突（或神经胶质突起）。过多的层粘连蛋白会导致这种反应过早发生。分化为神经元或神经胶质细胞的细胞大概不再迁移；因此，它们对异常细胞外ls/ls基质作出反应的区域远端的肠管不会被神经嵴衍生细胞定植。1975-2动物的分子缺陷尚不清楚，但似乎它干扰的不是神经嵴衍生细胞的迁移，而是它们随后沿着适合肠道的谱系进行的分化。由于Hox-1.4基因在整个肠道长度上均过度表达，而不仅仅是在异常节段，我们提出神经前体细胞长时间暴露于过表达Hox-1.4基因产物的细胞中，会使神经前体细胞对肠微环境对神经分化的影响无反应。因此，1975-2肠的异常区域是神经嵴衍生细胞最后定植的区域。
