Background & Aims

When the glial fibrillary acidic protein (GFAP) promoter is used to express cellular toxins that eliminate glia in mice, intestinal epithelial permeability and proliferation increase; this led to the concept that glia are required for maintenance of the gastrointestinal epithelium. Many enteric glia, however, particularly in the mucosa, do not express GFAP. In contrast, virtually all enteric glia express proteolipid protein 1 (PLP1). We investigated whether elimination of PLP1-expressing cells compromises epithelial maintenance or gastrointestinal motility.

Methods

We generated mice that express tamoxifen-inducible Cre recombinase under control of the Plp1 promoter and carry the diptheria toxin subunit A (DTA) transgene in the Rosa26 locus (Plp1^CreER;Rosa26^DTA mice). In these mice, PLP1-expressing glia are selectively eliminated without affecting neighboring cells. We measured epithelial barrier function and gastrointestinal motility in these mice and littermate controls, and analyzed epithelial cell proliferation and ultrastructure from their intestinal tissues. To compare our findings with those from previous studies, we also eliminated glia with ganciclovir in Gfap^HSV-TK mice.

Results

Expression of DTA in PLP1-expressing cells selectively eliminated enteric glia from the small and large intestines, but caused no defects in epithelial proliferation, barrier integrity, or ultrastructure. In contrast, administration of ganciclovir to Gfap^HSV-TK mice eliminated fewer glia but caused considerable non-glial toxicity and epithelial cell death. Elimination of PLP1-expressing cells did not reduce survival of neurons in the intestine, but altered gastrointestinal motility in female, but not male, mice.

Conclusions

Using the Plp1 promoter to selectively eliminate glia in mice, we found that enteric glia are not required for maintenance of the intestinal epithelium, but are required for regulation of intestinal motility in females. Previous observations supporting the concept that maintenance of the intestinal epithelium requires enteric glia can be attributed to non-glial toxicity in Gfap^HSV-TK mice and epithelial-cell expression of GFAP. Contrary to widespread notions, enteric glia are therefore not required for epithelial homeostasis. However, they regulate intestinal motility in a sex-dependent manner.

中文翻译：

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肠胶质调节胃肠运动，但维持小鼠上皮细胞不是必需的

背景与目标

当神经胶质原纤维酸性蛋白（GFAP）启动子用于表达消除小鼠胶质细胞的细胞毒素时，肠上皮的通透性和增殖会增加。这导致了维持胃肠上皮所需要的神经胶质的概念。但是，许多肠神经胶质细胞，特别是在粘膜中，不表达GFAP。相反，几乎所有肠神经胶质细胞都表达蛋白脂质蛋白1（PLP1）。我们调查了是否消除表达PLP1的细胞会损害上皮维持或胃肠动力。

方法

我们生成了在Plp1启动子控制下表达他莫昔芬诱导的Cre重组酶并在Rosa26基因座中携带白喉毒素亚基A（DTA）转基因的小鼠（Plp1 ^CreER ; Rosa26 ^DTA小鼠）。在这些小鼠中，表达PLP1的神经胶质细胞被有选择地消除，而不会影响邻近细胞。我们测量了这些小鼠和同窝仔对照中的上皮屏障功能和肠胃蠕动，并分析了其肠组织中的上皮细胞增殖和超微结构。为了将我们的发现与以前的研究进行比较，我们还用更昔洛韦在Gfap ^HSV-TK小鼠中消除了神经胶质。

结果

DTA在表达PLP1的细胞中的表达选择性地消除了小肠和大肠的肠神经胶质，但在上皮增殖，屏障完整性或超微结构方面未引起任何缺陷。相比之下，更昔洛韦对Gfap ^HSV-TK小鼠的给药消除了较少的神经胶质，但引起了相当大的非神经胶质毒性和上皮细胞死亡。消除表达PLP1的细胞不会降低肠道神经元的存活率，但会改变雌性小鼠（而非雄性小鼠）的肠胃蠕动。

结论

使用Plp1启动子选择性清除小鼠的胶质细胞，我们发现肠胶质细胞不是维持肠上皮细胞所必需的，而是调节雌性小鼠肠蠕动所必需的。先前的观点支持肠道上皮的维持需要肠神经胶质这一概念，这可以归因于Gfap ^HSV-TK小鼠的非神经胶质毒性和GFAP的上皮细胞表达。与普遍的观点相反，因此上皮稳态不需要肠神经胶质。但是，它们以性别依赖性方式调节肠蠕动。