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  • The ATX LPA signaling axis has been implicated in a

    2022-11-07

    The ATX–LPA signaling “axis” [5] has been implicated in a perplexing variety of physiological and pathophysiological processes, including vascular and neural development [5], [26], [27], [28], [29], tumor progression and metastasis [30], [31], lymphocyte trafficking [22], bone development [32], neuropathic pain [33], pulmonary fibrosis [34], fat mass regulation [35], cholestatic pruritus [36], fetal hydrocephalus [37] and chronic inflammation [38]. In this review, we will discuss the vital role of ATX–LPA receptor signaling in vertebrate development.
    Expression of ATX and LPA receptors during mammalian development The temporal and spatial expression pattern of ATX in the developing mouse embryo is highly dynamic. Using whole-mount in situ hybridization, Ohuchi et al. [39] found that regions of ATX expression can be divided in two categories: (i) local signaling centers during neural development (e.g. midbrain regions and the floor plate of the neural tube), and (ii) organ primordia in which epithelial-mesenchymal interaction is essential for organogenesis (e.g. skin appendages, choroid plexus epithelia, face primordia and limb buds). At E8.5, ATX expression was detected in the anterior folds of the neural tube, which is still open at that stage, and at the most posterior region of the midbrain; but at E9.0-E9.5, ATX expression was strongly reduced in that exportin region. At E10.5, prominent ATX expression was found at the floor plate of the neural tube, in agreement with an earlier study [40]. At later stages (E11.5-E12.5), ATX was strongly expressed in nasal processes, the developing ear, mammary glands and the developing intestine. Thereafter, at E13.5, ATX expression is dominant in mesenchymal tissues and choroid plexus epithelia [39], [40], where cerebrospinal fluid is produced. As from E16.5, ATX mRNA is detectable in kidney and smooth muscle, while ATX remains highly expressed in choroid plexus epithelia until birth [40]. The extra-embryonic visceral yolk sac is the first site where hematopoiesis and vasculogenesis occurs in the mouse. Diffuse ATX expression is observed in extra-embryonic regions at E7.0. Shortly thereafter, at E7.5, ATX appeared in the yolk sac and anterior head processes [28]. At E8.5, ATX expression is found in the visceral endoderm cells that surround the yolk sac [27]. At all embryonic stages, high ATX protein levels and lysoPLD activity were detected in amniotic fluid [27], a growth factor-rich fluid that is “inhaled” and “exhaled” by the fetus in order to develop normally. Also in sheep embryos, ATX expression is increased at the time of yolk sac formation [41]. Our own studies indicate that ATX and four distinct LPA receptors (Lpar) are already detectable during early post-implantation stages (E6.5), that are prior to yolk sac vascular development [26]. Expression of ATX and LPA receptors increased during the stages of vessel formation and expansion (E8.5 to E10.5) [26]. A detailed expression analysis of Lpar in E8.5 to E12.5 mouse embryos revealed an overlap with the expression of ATX [42]. At E8.5, Lpra4 was detected in the allantois, which undergoes vasculogenesis to form the mature umbilical artery and vein, and in the midbrain-hindbrain boundary. Lpar1 was detected in the neural tube, and Lpar1, Lpar2, Lpar4 and Lpar5 in the anterior neural folds [42]. Dynamic expression of ATX in conjunction with distinct LPA receptors during midgestation is consistent with an important role for ATX–LPA signaling in morphogenesis, patterning and organogenesis.
    Important insights into the role of ATX in embryonic development have come from knockout studies in mice. Several strategies have been used to generate Enpp2 null mice. One strategy involved deletion of exons 6 and 7, which encode the catalytic domain of ATX [26], [28]. Others deleted exons 1 and 2, which include the initiation codon and the first 45 amino acids [27], [29]. Knock-in mice containing the catalytically dead ATX(T210A) mutant have also been generated [43]. All Enpp2(−/−) mice die during early development, independent of genetic background, whereas the heterozygous animals are phenotypically normal. It is noteworthy that Enpp2(+/−) heterozygous mice possess half as much plasma LPA as their normal littermates [26], [27], consistent with ATX being the major LPA-producing enzyme in vivo and, furthermore, indicating that ATX activity is not upregulated to compensate for the Enpp2 null allele.