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Spatiotemporal expression pattern of progranulin in embryo implantation and placenta formation suggests a role in cell proliferation, remodeling, and angiogenesis

Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, 3200 Sicotte, St-Hyacinthe, Québec, Canada J2S 7C6 and¹ Endocrine Research Laboratories, Department of Medicine, Royal Victoria Hospital, McGill University, 687 ave. des Pins Ouest, Room L2.05, Montreal, Quebec, Canada H3A 1A1

Correspondence should be addressed to J A Desmarais; Email: joelle.desmarais{at}umontreal.ca

J A Desmarais and M Cao contributed equally to this work

Embryo implantation in the mink is preceded by a variable but obligate period of delay in development. Under the influence of progesterone and unknown luteal factors, the mink embryo implants 11–13 days following its exit from diapause. Recent work suggests that progranulin, a growth factor and secreted glycoprotein, is involved in trophoblast proliferation, placental development and endometrial differentiation in the mouse. Using the mink model of delayed implantation and endotheliochorial placentation, we examined the spatiotemporal distribution of progranulin in trophoblast and endometrium during pre- and early post-implantation gestation in vivo. A partial sequence of the mink progranulin gene was cloned and sequenced. Comparative sequence analysis revealed that exons 1 and 2 of mink progranulin share 86.6, 82.4, and 94.9% of nucleic acid sequence identity with the human, mouse, and dog sequences respectively, and indicated that the invariable residues of the cysteine-rich motifs of progranulin are well conserved in the mink sequence. By in situ hybridization, we show that mink progranulin transcript is present in the cytotrophoblast and in epithelial and stromal endometrial cells at the site of implantation and during early placental formation. Immunohistochemistry revealed the progranulin protein to be strongly expressed in endometrial luminal and glandular epithelium around the time of implantation. In the incipient labyrinth, progranulin expression is localized to cytotrophoblasts and fetal capillaries, as well as to the hypertrophied maternal endothelial cells. This study demonstrates that high levels of progranulin expression correspond to active cell proliferation, remodeling, and angiogenesis occurring during the establishment of the placenta in the mink.