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

ABSTRACT 25 Embryo implantation in the mink is preceded by a variable but obligate period of delay in 26 development. Under the influence of progesterone and unknown luteal factors, the mink embryo 27 implants 11-13 days following its exit from diapause. Recent work suggests that progranulin, a 28 growth factor and secreted glycoprotein, is involved in trophoblast proliferation, placental 29 development and endometrial differentiation in the mouse. Using the mink model of delayed 30 implantation and endotheliochorial placentation, we examined the spatio-temporal distribution of 31 progranulin in trophoblast and endometrium during pre- and early post-implantation gestation in 32 vivo. A partial sequence of the mink progranulin gene was cloned and sequenced. Comparative 33 sequence analysis revealed that exons 1 and 2 of mink progranulin share 86.6 %, 82.4%, 94.9% 34 nucleic acid sequence identity with the human, mouse and dog sequences respectively, and 35 indicated that the invariable residues of the cysteine-rich motifs of progranulin are well conserved 36 in the mink sequence. By in situ hybridization, we show that mink progranulin transcript is 37 present in the cytotrophoblast and in epithelial and stromal endometrial cells at the site of 38 implantation and during early placental formation. Immunohistochemistry revealed the 39 progranulin protein to be strongly expressed in endometrial luminal and glandular epithelium 40 around the time of implantation. In the incipient labyrinth, progranulin expression is localised to 41 cytotrophoblasts, fetal capillaries, as well as to the hypertrophied maternal endothelial cells. This 42 study demonstrates that high levels of progranulin expression correspond to active cell 43 proliferation, remodelling and angiogenesis occurring during the establishment of the placenta in 44 the mink.