The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning
The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning
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DOI：
10.1242/dev.00635
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发表时间：
2003-10-01
期刊：
影响因子：
4.6
通讯作者：
Stewart, CL
中科院分区：
文献类型：
--
作者：
Escalante-Alcalde, D;Hernandez, L;Stewart, CL
生物活性磷脂包括鞘氨醇-1-磷酸、溶血磷脂酸、神经酰胺及其衍生物，在培养过程中调节多种细胞功能，如增殖、凋亡和分化。这些脂质及其产物的可利用性受脂质磷酸酶(LPP)的调节。在这里，我们发现缺乏LPP3的小鼠胚胎不能形成绒毛尿囊胎盘和卵黄囊血管系统。一组胚胎还显示出前后轴缩短和轴结构频繁重复，这些结构与轴蛋白缺乏相关的表型惊人地相似，轴蛋白缺乏是Wnt信号的关键调节因子。LPP3缺失导致β-连环素介导的TCF转录显著增加，而LPP3水平升高则抑制β-连环素介导的TCF转录。LPP3还抑制了非洲爪哇胚胎的轴复制，并导致了轻微的腹壁发育。尽管LPP3缺失的成纤维细胞显示出生物活性磷脂水平的改变，与LPP3磷酸酶活性的丧失一致，但LPP3的突变形式，特别是缺乏磷酸酶活性的突变形式，能够抑制β-连环素介导的TCF转录，也抑制轴复制，尽管不如完整的LPP3有效。这些结果表明，LPP3对绒毛尿囊膜胎盘和胚胎外血管的形成是必不可少的。LPP3还可能通过影响典型的Wnt信号通路来调节原肠形成和轴的形成。LPP3磷酸酶活性的确切生化作用及其对β-连环蛋白介导的TCF转录的影响尚不明确。
Bioactive phospholipids, which include sphingosine-1-phosphate, lysophosphatidic acid, ceramide and their derivatives regulate a wide variety of cellular functions in culture such as proliferation, apoptosis and differentiation. The availability of these lipids and their products is regulated by the lipid phosphate phosphatases (LPPs). Here we show that mouse embryos deficient for LPP3 fail to form a chorio-allantoic placenta and yolk sac vasculature. A subset of embryos also show a shortening of the anterior-posterior axis and frequent duplication of axial structures that are strikingly similar to the phenotypes associated with axin deficiency, a critical regulator of Wnt signaling. Loss of LPP3 results in a marked increase in beta-catenin-mediated TCF transcription, whereas elevated levels of LPP3 inhibit beta-catenin-mediated TCF transcription. LPP3 also inhibits axis duplication and leads to mild ventralization in Xenopus embryo development. Although LPP3 null fibroblasts show altered levels of bioactive phospholipids, consistent with loss of LPP3 phosphatase activity, mutant forms of LPP3, specifically lacking phosphatase activity, were able to inhibit beta-catenin-mediated TCF transcription and also suppress axis duplication, although not as effectively as intact LPP3. These results reveal that LPP3 is essential to formation of the chorio-allantoic placenta and extra-embryonic vasculature. LPP3 also mediates gastrulation and axis formation, probably by influencing the canonical Wnt signaling pathway. The exact biochemical roles of LPP3 phosphatase activity and its undefined effect on beta-catenin-mediated TCF transcription remain to be determined.