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This Article Full Text Full Text (PDF) All Versions of this Article: 71/6/2003    most recent biolreprod.104.031864v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brown, N. Articles by Reese, J. Search for Related Content PubMed PubMed Citation Articles by Brown, N. Articles by Reese, J. Agricola Articles by Brown, N. Articles by Reese, J.

Embryo-Uterine Interactions via the Neuregulin Family of Growth Factors During Implantation in the Mouse¹

Division of Reproductive and Developmental Biology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2370

Neuregulins (NRGs) are cell-signaling molecules with recognized roles in cancer and development, but little is known about their role in embryo implantation. Among representative NRG-1 isoforms, neu differentiation factor (NDF, type I) is expressed in the female reproductive tract and is localized to the implantation site. Here, we show that sensory and motor neuron-derived factor (SMDF, type III) is expressed in the uterine subepithelial stroma around the blastocyst and is only upregulated at the time of implantation. The cellular distribution of SMDF is similar to that of NDF and requires an implantation-competent blastocyst. The glial growth factor (GGF, type II) isoform of NRG-1 and the NRG-2 and NRG-3 genes were not expressed in the peri-implantation uterus, as determined by reverse transcription-polymerase chain reaction or in situ hybridization. In contrast to the cellular expression pattern of NDF and SMDF, NRG-4 was present in the luminal and glandular epithelium throughout the uterus during the preimplantation period. Expression of NRG-4 declined in the uterine luminal epithelium during implantation but persisted in the glandular epithelium through Day 8 of pregnancy. Studies in ovariectomized mice showed that NRG-4 is a progesterone-regulated gene, with partial augmentation by estrogen. We also observed upregulation of the erbB2 and erbB3 receptors at the blastocyst stage of embryo development. Together, these findings suggest that a distinct subset of NRGs participates in the signaling network that directs embryo implantation. Upregulation of embryonic erbB2/ erbB3 in the blastocyst trophectoderm and induction of certain NRG-1 isoforms with blastocyst activation help to define additional aspects of the embryo-uterine cross-talk that underlies the implantation process.

¹ Supported by NIH grants HD42636 and HD44741 to B.C.P., ES07814 and HD37830 to S.K.D., and HD37667 and HD40221 to J.R.

² Correspondence: Jeff Reese, D-4106 Medical Center North, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2370. FAX: 615 322 4704; jeff.re-ese{at}vanderbilt.edu

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