XB-ART-4825Development October 1, 2003; 130 (19): 4623-37.
The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning.
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.
PubMed ID: 12925589
Article link: Development
Genes referenced: otx2 pax6 plpp3 wnt3a wnt8a
Article Images: [+] show captions
|Fig. 9. Effect of LPP3 in Xenopus axial patterning. (A-C) Effect of murine LPP3 mRNA injection in Xenopus embryo development. Stage 36 larvae (A) uninjected, (B) injected dorsally or (C) ventrally with 1 ng of mLPP3 mRNA. Inserts show translated LPP3 protein. Note that only the larvae injected dorsally had abnormal anterior development. (D-H) In situ hybridization of un-injected and dorsally injected Xenopus embryos with markers for anterior development (stage 22). (D,E) Xotx2 detection in uninjected (bottom) and dorsally injected (top) embryos. Some injected embryos lacked (D) or had reduced (E) Xotx2 expression. Reduced and fused eyes can be observed in the injected embryo (E, arrow). (F) Xpax6 detection in uninjected (bottom) and dorsally injected (top) embryos. Injected embryos lacked distinguishable eye staining. (G) Embryos injected ventrally with Xwnt3a show a duplicated axis. (H) Co-injection of mLPP3 with Xwnt3a mRNA rescues secondary axis formation but results in a weak dorsalizalized phenotype. (I) Axis duplication induced by ventral injection of Xwnt8. (J) Co-injection of Xwnt8 with LPP3 mRNA inhibited axis duplication, but the embryos still retained a weak dorsalization phenotype.|