Functional interactions between the LRP6 WNT co-receptor and folate supplementation
Functional interactions between the LRP6 WNT co-receptor and folate supplementation
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DOI：
10.1093/hmg/ddq384
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发表时间：
2010-12-01
影响因子：
3.5
通讯作者：
Ross, M. Elizabeth
中科院分区：
文献类型：
--
作者：
Gray, Jason D.;Nakouzi, Ghunwa;Ross, M. Elizabeth
弯尾（Cd）小鼠在Lrp 6（经典WNT信号传导的共受体）中具有功能获得性突变，并且是神经管缺陷（NTD）的模型，可通过膳食叶酸（FA）补充剂预防。FA反应是否反映了FA对LRP 6功能的直接影响，在LRP 6缺陷胚胎中进行产前补充。与对照组（2 ppm FA）相比，富FA（10 ppm）饲料降低了所有窝仔中出生缺陷的发生率，但这是通过增加Lrp 6（-/-）胚胎的早期致死率而实现的，同时实际上增加了胚胎第10-13天（E10-13）存活的空胎中的NTD。在E10时，与野生型胚胎相比，纯合子Lrp 6（-/-）突变体的颅神经褶皱增殖减少，FA补充增加了野生型神经上皮细胞的增殖，但突变体神经上皮细胞的增殖没有增加。典型的WNT活性降低LRP 6缺陷中脑-后脑在E9.5，证明在体内的TCF/LEF-报告基因转基因。培养基中的FA水平调节NIH 3 T3细胞中的典型WNT响应，这表明尽管FA是最佳WNT信号传导所需的，但即使是适度的FA升高也会减弱LRP 5/6依赖的典型WNT响应。胚胎和成人的基因表达分析显示，靶向Lrp 6缺乏和FA补充之间存在显著的相互作用，特别是对线粒体功能、叶酸和甲硫氨酸代谢、WNT信号传导和细胞骨架调节，这些共同涉及支持细胞增殖、形态和分化的相关信号传导和代谢途径。我们建议，FA补充救援LRP 6（镉/镉）胎儿正常化过度活跃的WNT活性，而在LRP 6缺陷的胚胎，增加FA进一步减弱减少WNT活性，从而损害发展。
Crooked tail (Cd) mice bear a gain-of-function mutation in Lrp6, a co-receptor for canonical WNT signaling, and are a model of neural tube defects (NTDs), preventable with dietary folic acid (FA) supplementation. Whether the FA response reflects a direct influence of FA on LRP6 function was tested with prenatal supplementation in LRP6-deficient embryos. The enriched FA (10 ppm) diet reduced the occurrence of birth defects among all litters compared with the control (2 ppm FA) diet, but did so by increasing early lethality of Lrp6(-/-) embryos while actually increasing NTDs among nulls alive at embryonic days 10-13 (E10-13). Proliferation in cranial neural folds was reduced in homozygous Lrp6(-/-) mutants versus wild-type embryos at E10, and FA supplementation increased proliferation in wild-type but not mutant neuroepithelia. Canonical WNT activity was reduced in LRP6-deficient midbrain-hindbrain at E9.5, demonstrated in vivo by a TCF/LEF-reporter transgene. FA levels in media modulated the canonical WNT response in NIH3T3 cells, suggesting that although FA was required for optimal WNT signaling, even modest FA elevations attenuated LRP5/6-dependent canonical WNT responses. Gene expression analysis in embryos and adults showed striking interactions between targeted Lrp6 deficiency and FA supplementation, especially for mitochondrial function, folate and methionine metabolism, WNT signaling and cytoskeletal regulation that together implicate relevant signaling and metabolic pathways supporting cell proliferation, morphology and differentiation. We propose that FA supplementation rescues Lrp6(Cd/Cd) fetuses by normalizing hyperactive WNT activity, whereas in LRP6-deficient embryos, added FA further attenuates reduced WNT activity, thereby compromising development.