RESUMO
Autotaxin (ATX), or nucleotide pyrophosphatase-phosphodiesterase 2, is a secreted lysophospholipase D that promotes cell migration, metastasis, and angiogenesis. ATX generates lysophosphatidic acid (LPA), a lipid mitogen and motility factor that acts on several G protein-coupled receptors. Here we report that ATX-deficient mice die at embryonic day 9.5 (E9.5) with profound vascular defects in yolk sac and embryo resembling the Galpha13 knockout phenotype. Furthermore, at E8.5, ATX-deficient embryos showed allantois malformation, neural tube defects, and asymmetric headfolds. The onset of these abnormalities coincided with increased expression of ATX and LPA receptors in normal embryos. ATX heterozygous mice appear healthy but show half-normal ATX activity and plasma LPA levels. Our results reveal a critical role for ATX in vascular development, indicate that ATX is the major LPA-producing enzyme in vivo, and suggest that the vascular defects in ATX-deficient embryos may be explained by loss of LPA signaling through Galpha13.
Assuntos
Vasos Sanguíneos/anormalidades , Embrião de Mamíferos/anormalidades , Genes Letais , Lisofosfolipídeos/metabolismo , Complexos Multienzimáticos/metabolismo , Fosfodiesterase I/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Animais , Vasos Sanguíneos/enzimologia , Embrião de Mamíferos/irrigação sanguínea , Embrião de Mamíferos/enzimologia , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Lisofosfolipídeos/sangue , Camundongos , Camundongos Knockout , Complexos Multienzimáticos/genética , Fosfodiesterase I/genética , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismoRESUMO
Although in mice, the dynamics of gene expression during heart development is well characterized, information on humans is scarce due to the limited availability of material. Here, we analyzed the transcriptional distribution of Mlc-2a, Mlc-1v, Mlc-2v, and atrial natriuretic factor (ANF) in human embryonic hearts between 7 and 18 weeks of gestation and in healthy and hypertrophic adult hearts by in situ hybridization and compared expression with that in mice. Strikingly, Mlc-2a, Mlc-1v, and ANF, which are essentially chamber-restricted in mice by mid-gestation, showed a broader distribution in humans. On the other hand, Mlc-2v may prove to be an adequate ventricular marker in humans in contrast to mouse. This study emphasizes the importance of careful comparative human-animal analyses during embryonic development and adulthood, as avoiding erroneous extrapolations may be critical to develop new and successful myocardial replacement therapies.