title: The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning.
abstract: 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.
authors.affiliation: Cancer and Developmental Biology Laboratory, Division of Basic Science, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Escalante-Alcalde
authors.forename: Lidia
authors.initials: L
authors.lastname: Hernandez
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Stunff
authors.forename: Ryu
authors.initials: R
authors.lastname: Maeda
authors.forename: Hyun-Shik
authors.initials: HS
authors.lastname: Lee
authors.lastname: Jr-Gang-Cheng
authors.forename: Vicki A
authors.initials: VA
authors.lastname: Sciorra
authors.forename: Ira
authors.initials: I
authors.lastname: Daar
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D002478:Cells, Cultured; D046508:Culture Techniques; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D004625:Embryo, Nonmammalian; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005838:Genotype; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology; D009389:Neovascularization, Pathologic; D010641:Phenotype; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D010920:Placenta / Q000098:blood supply / Q000473:pathology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology; D015017:Yolk Sac / Q000098:blood supply / Q000473:pathology; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D010743:Phospholipids; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D010711:Phosphatidate Phosphatase; C479566:Plpp3 protein, mouse