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 β-catenin-mediated TCF transcription, whereas elevated levels of LPP3 inhibit β-catenin-mediated TCF transcription. LPP3 also inhibits axis duplication and leads to mild ventralization in Xenopusembryo 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 β-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 β-catenin-mediated TCF transcription remain to be determined.

Lipid Phosphate Phosphatases Regulate Lysophosphatidic Acid Production and Signaling in Platelets

“…Furthermore, there are hints that LPPs may have actions that are independent of their catalytic activities. Effects of LPP3 inactivation in mice are similar to those seen when wnt signaling is up-regulated and LPP3 inhibits wnt signaling in cultured cells (27). LPP3 has also been shown to serve as an integrin ligand that regulates cell-cell interactions through a unique RGD sequence in the second extracellular loop (26).…”

“…Although genetic inactivation of LPP2 in mice produces no obvious phenotype, inactivation of the LPP3 gene results in early embryonic lethality resulting from defects in vascularization and patterning (27,38). Furthermore, there are hints that LPPs may have actions that are independent of their catalytic activities.…”

“…Newly synthesized chemical inhibitors identify LPP1 as a global regulator of LPA production and signaling in platelets. The dual function of LPP1 as a regulator of both LPA production and responsiveness may explain the complex and pleiotropic phenotypes associated with overexpression, misexpression, or down-regulation of this class of enzymes in many systems (19,21,(25)(26)(27)(28).…”

Role of Sphingosine-1-phosphate Phosphatase 1 in Epidermal Growth Factor-induced Chemotaxis

“…Both belong to the family of type 2 lipid phosphate phosphohydrolases (LPPs) (17, 18) which are magnesium-independent, membrane-associated, and N-ethylmaleimide-insensitive. Although specific biological roles for the LPPs have not yet been established, the Drosophila gene wunen, which encodes a homologue of LPP1 and LPP2, negatively regulates primordial germ cell migration (19); LPP3 mediates gastrulation and axis formation, probably by influencing the canonical Wnt signaling pathway (20). Except for the conserved residues within three domains present in the active sites of LPPs (17), the two S1P phosphatases have little overall homology to other known LPPs and, in contrast to the broad specificity of the other LPPs (18), are specific sphingoid base phosphate phosphatases.…”

Lipid phosphate phosphatase inhibitors locally amplify lysophosphatidic acid LPA1 receptor signalling in rat brain cryosections without affecting global LPA degradation

“…Study with LPP1 knockout mice indicated that LPP1 plays a role in regulating the degradation of circulating LPA in vivo but that study failed to disrupt the LPP1 encoding gene in the brain, obscuring the function of LPP1 in the nervous system [46]. Knockout of LPP3 turned out to be embryonically lethal [45] whereas in vitro studies using cell lines lacking LPP3 address involvement of LPP3 in early neural development [47]. The LPPs are likely to be involved in LPA dephosphorylation in brain cryosections, as brain sections efficiently generate P i from exogenous LPA largely in a NEM resistant and Mg 2+ -independent way.…”