Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (
María Emilia Solano, Mirka Katharina Kowal, Greta Eugenia O’Rourke, Andrea Kristina Horst, Kathrin Modest, Torsten Plösch, Roja Barikbin, Chressen Catharina Remus, Robert G. Berger, Caitlin Jago, Hoang Ho, Gabriele Sass, Victoria J. Parker, John P. Lydon, Francesco J. DeMayo, Kurt Hecher, Khalil Karimi, Petra Clara Arck
Increased synthesis of cervical hyaluronan (HA) from early to late pregnancy has long been proposed to play an essential role in disorganization of the collagen-rich extracellular matrix to allow for maximal compliance and dilation of the cervix during the birth process. Here, we show that HA is not essential for increased cervical distensibility during late pregnancy. Rather, cervicovaginal HA plays an unanticipated important role in epithelial barrier protection of the lower reproductive tract. Specifically, HA depletion in the cervix and vagina resulted in inappropriate differentiation of epithelial cells, increased epithelial and mucosal permeability, and strikingly increased preterm birth rates in a mouse model of ascending vaginal infection. Collectively, these findings revealed that although HA is not obligatory for cervical compliance, it is crucial for maintaining an epithelial and mucosal barrier to limit pathogen infiltration of the lower reproductive tract during pregnancy and thereby is protective against infection-mediated preterm birth.
Yucel Akgul, R. Ann Word, Laura M. Ensign, Yu Yamaguchi, John Lydon, Justin Hanes, Mala Mahendroo
Reduced trophoblast invasion and vascular conversion in decidua are thought to be the primary defect of common pregnancy disorders including preeclampsia and fetal growth restriction. Genetic studies suggest these conditions are linked to combinations of polymorphic killer cell Ig-like receptor (
Shiqiu Xiong, Andrew M. Sharkey, Philippa R. Kennedy, Lucy Gardner, Lydia E. Farrell, Olympe Chazara, Julien Bauer, Susan E. Hiby, Francesco Colucci, Ashley Moffett
There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of
Jeeyeon Cha, Amanda Bartos, Mahiro Egashira, Hirofumi Haraguchi, Tomoko Saito-Fujita, Emma Leishman, Heather Bradshaw, Sudhansu K. Dey, Yasushi Hirota
Macrophages are prominent in the uterus and ovary at conception. Here we utilize the
Alison S. Care, Kerrilyn R. Diener, Melinda J. Jasper, Hannah M. Brown, Wendy V. Ingman, Sarah A. Robertson
Abnormalities in cell-cell communication and growth factor signaling pathways can lead to defects in maternal-fetal interactions during pregnancy, including immunologic rejection of the fetal/placental unit. In this study, we discovered that bone morphogenetic protein receptor type 2 (BMPR2) is essential for postimplantation physiology and fertility. Despite normal implantation and early placental/fetal development, deletion of
Takashi Nagashima, Qinglei Li, Caterina Clementi, John P. Lydon, Francesco J. DeMayo, Martin M. Matzuk
The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.
Manyu Li, Nicole M.J. Schwerbrock, Patricia M. Lenhart, Kimberly L. Fritz-Six, Mahita Kadmiel, Kathleen S. Christine, Daniel M. Kraus, Scott T. Espenschied, Helen H. Willcockson, Christopher P. Mack, Kathleen M. Caron
Spermatogonial stem cells (SSCs) capable of self-renewal and differentiation are the foundation for spermatogenesis. Although several factors important for these processes have been identified, the fundamental mechanisms regulating SSC self-renewal and differentiation remain unknown. Here, we investigated a role for the Foxo transcription factors in mouse spermatogenesis and found that Foxo1 specifically marks mouse gonocytes and a subset of spermatogonia with stem cell potential. Genetic analyses showed that Foxo1 was required for both SSC homeostasis and the initiation of spermatogenesis. Combined deficiency of Foxo1, Foxo3, and Foxo4 resulted in a severe impairment of SSC self-renewal and a complete block of differentiation, indicating that Foxo3 and Foxo4, although dispensable for male fertility, contribute to SSC function. By conditional inactivation of 3-phosphoinositide–dependent protein kinase 1 (Pdk1) and phosphatase and tensin homolog (Pten) in the male germ line, we found that PI3K signaling regulates Foxo1 stability and subcellular localization, revealing that the Foxos are pivotal effectors of PI3K-Akt signaling in SSCs. We also identified a network of Foxo gene targets — most notably Ret — that rationalized the maintenance of SSCs by the Foxos. These studies demonstrate that Foxo1 expression in the spermatogenic lineage is intimately associated with the stem cell state and revealed what we believe to be novel Foxo-dependent mechanisms underlying SSC self-renewal and differentiation, with implications for common diseases, including male infertility and testicular cancer, due to abnormalities in SSC function.
Meredith J. Goertz, Zhuoru Wu, Teresa D. Gallardo, F. Kent Hamra, Diego H. Castrillon
During intrauterine life, the mammalian embryo survives via its physical connection to the mother. The uterine decidua, which differentiates from stromal cells after implantation in a process known as decidualization, plays essential roles in supporting embryonic growth before establishment of the placenta. Here we show that female mice lacking death effector domain–containing protein (DEDD) are infertile owing to unsuccessful decidualization. In uteri of Dedd–/– mice, development of the decidual zone and the surrounding edema after embryonic implantation was defective. This was subsequently accompanied by disintegration of implantation site structure, leading to embryonic death before placentation. Polyploidization, a hallmark of mature decidual cells, was attenuated in DEDD-deficient cells during decidualization. Such inefficient decidualization appeared to be caused by decreased Akt levels, since polyploidization was restored in DEDD-deficient decidual cells by overexpression of Akt. In addition, we showed that DEDD associates with and stabilizes cyclin D3, an important element in polyploidization, and that overexpression of cyclin D3 in DEDD-deficient cells improved polyploidization. These results indicate that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice.
Mayumi Mori, Miwako Kitazume, Rui Ose, Jun Kurokawa, Kaori Koga, Yutaka Osuga, Satoko Arai, Toru Miyazaki
Sirtuins are a phylogenetically conserved NAD+-dependent protein deacetylase/ADP-ribosyltransferase family implicated in diverse biological processes. Several family members localize to mitochondria, the function of which is thought to determine the developmental potential of preimplantation embryos. We have therefore characterized the role of sirtuins in mouse preimplantation development under in vitro culture conditions. All sirtuin members were expressed in eggs, and their expression gradually decreased until the blastocyst stage. Treatment with sirtuin inhibitors resulted in increased intracellular ROS levels and decreased blastocyst formation. These effects were recapitulated by siRNA-induced knockdown of Sirt3, which is involved in mitochondrial energy metabolism, and in Sirt3–/– embryos. The antioxidant N-acetyl-L-cysteine and low-oxygen conditions rescued these adverse effects. When Sirt3-knockdown embryos were transferred to pseudopregnant mice after long-term culture, implantation and fetal growth rates were decreased, indicating that Sirt3-knockdown embryos were sensitive to in vitro conditions and that the effect was long lasting. Further experiments revealed that maternally derived Sirt3 was critical. Sirt3 inactivation increased mitochondrial ROS production, leading to p53 upregulation and changes in downstream gene expression. The inactivation of p53 improved the developmental outcome of Sirt3-knockdown embryos, indicating that the ROS-p53 pathway was responsible for the developmental defects. These results indicate that Sirt3 plays a protective role in preimplantation embryos against stress conditions during in vitro fertilization and culture.
Yumiko Kawamura, Yasunobu Uchijima, Nanao Horike, Kazuo Tonami, Koichi Nishiyama, Tomokazu Amano, Tomoichiro Asano, Yukiko Kurihara, Hiroki Kurihara