scholarly journals Uterine activin receptor-like kinase 5 is crucial for blastocyst implantation and placental development

2015 ◽  
Vol 112 (36) ◽  
pp. E5098-E5107 ◽  
Author(s):  
Jia Peng ◽  
Diana Monsivais ◽  
Ran You ◽  
Hua Zhong ◽  
Stephanie A. Pangas ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Nk Cell ◽  
Conditional Knockout ◽  
Major Type ◽  
Female Reproduction ◽  
Placental Development ◽  
Activin Receptor ◽  
Decidual Cells ◽  
Unk Cells ◽  
Receptor Like Kinase

Members of the transforming growth factor β (TGF-β) superfamily are key regulators in most developmental and physiological processes. However, the in vivo roles of TGF-β signaling in female reproduction remain uncertain. Activin receptor-like kinase 5 (ALK5) is the major type 1 receptor for the TGF-β subfamily. Absence of ALK5 leads to early embryonic lethality because of severe defects in vascular development. In this study, we conditionally ablated uterine ALK5 using progesterone receptor-cre mice to define the physiological roles of ALK5 in female reproduction. Despite normal ovarian functions and artificial decidualization in conditional knockout (cKO) mice, absence of uterine ALK5 resulted in substantially reduced female reproduction due to abnormalities observed at different stages of pregnancy, including implantation defects, disorganization of trophoblast cells, fewer uterine natural killer (uNK) cells, and impairment of spiral artery remodeling. In our microarray analysis, genes encoding proteins involved in cytokine–cytokine receptor interactions and NK cell-mediated cytotoxicity were down-regulated in cKO decidua compared with control decidua. Flow cytometry confirmed a 10-fold decrease in uNK cells in cKO versus control decidua. According to these data, we hypothesize that TGF-β acts on decidual cells via ALK5 to induce expression of other growth factors and cytokines, which are key regulators in luminal epithelium proliferation, trophoblast development, and uNK maturation during pregnancy. Our findings not only generate a mouse model to study TGF-β signaling in female reproduction but also shed light on the pathogenesis of many pregnancy complications in human, such as recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction.

scholarly journals The Autophagy Gene Atg16L1 is Necessary for Endometrial Decidualization

Endocrinology ◽  
2019 ◽  
Vol 161 (1) ◽  
Author(s):  
Arin K Oestreich ◽  
Sangappa B Chadchan ◽  
Pooja Popli ◽  
Alexandra Medvedeva ◽  
Marina N Rowen ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Implantation Rate ◽  
Conditional Knockout ◽  
Uterine Receptivity ◽  
Placental Development ◽  
Human Escs ◽  
Embryo Survival ◽  
Autophagy Gene ◽  
Decidual Cells

Abstract Uterine receptivity is critical for establishing and maintaining pregnancy. For the endometrium to become receptive, stromal cells must differentiate into decidual cells capable of secreting factors necessary for embryo survival and placental development. Although there are multiple reports of autophagy induction correlated with endometrial stromal cell (ESC) decidualization, the role of autophagy in decidualization has remained elusive. To determine the role of autophagy in decidualization, we utilized 2 genetic models carrying mutations to the autophagy gene Atg16L1. Although the hypomorphic Atg16L1 mouse was fertile and displayed proper decidualization, conditional knockout in the reproductive tract of female mice reduced fertility by decreasing the implantation rate. In the absence of Atg16L1, ESCs failed to properly decidualize and fewer blastocysts were able to implant. Additionally, small interfering RNA knock down of Atg16L1 was detrimental to the decidualization response of human ESCs. We conclude that Atg16L1 is necessary for decidualization, implantation, and overall fertility in mice. Furthermore, considering its requirement for human endometrial decidualization, these data suggest Atg16L1 may be a potential mediator of implantation success in women.

scholarly journals Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor

2007 ◽  
Vol 195 (1) ◽  
pp. 95-103 ◽  
Author(s):  
Nina Renlund ◽  
Francis H O’Neill ◽  
LiHua Zhang ◽  
Yisrael Sidis ◽  
Jose Teixeira
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Type I ◽  
Type Ii ◽  
Activin Receptor ◽  
Activin Signaling ◽  
Endogenous Expression ◽  
Receptor Like Kinase

Activin receptor-like kinase-2 (Alk2) has been shown to be a promiscuous type I receptor for the transforming growth factor β (TGFβ) family of growth and differentiation factors, such as activin, bone morphogenetic proteins, and Müllerian inhibiting substance (MIS). We have studied the putative role of Alk2 in activin signaling using MA-10 cells, a mouse transformed Leydig cell line, in which endogenous expression of cytochrome P450 c17 hydroxylase/C17–20 lyase mRNA is inhibited by both MIS and activin A. Overexpression of Alk2 in MA-10 cells inhibited the activation of the activin-responsive CAGA-luciferase reporter and, conversely, transfection of siRNA for Alk2 increased the response. In contrast, overexpression of the MIS type II receptor in MA-10 cells increased the activin-mediated induction of CAGA-luciferase approximately fivefold, which we hypothesized occurs by MIS type II receptor sequestering endogenous Alk2. Binding experiments with 125I-labeled activin show that the underlying mechanism of Alk2-mediated inhibition of activin signaling involves Alk2 blocking the access of activin to its type II receptor, which we show can bind Alk2 in the absence of ligand. These results show that the complement of other type I receptors in addition to the ligand-specific type I receptor can provide an important mechanism for modulating cell-specific responses to members of the TGFβ family.

scholarly journals Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function

2016 ◽  
Vol 44 (4) ◽  
pp. 1142-1149 ◽  
Author(s):  
Amaya García de Vinuesa ◽  
Matteo Bocci ◽  
Kristian Pietras ◽  
Peter ten Dijke
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
New Combination ◽  
Current Status ◽  
Human Antibody ◽  
Type I ◽  
Activin Receptor ◽  
Alternative Pathways ◽  
Receptor Like Kinase

Angiogenesis is a hallmark of cancer and is now a validated therapeutic target in the clinical setting. Despite the initial success, anti-angiogenic compounds impinging on the vascular endothelial growth factor (VEGF) pathway display limited survival benefits in patients and resistance often develops due to activation of alternative pathways. Thus, finding and validating new targets is highly warranted. Activin receptor-like kinase (ALK)1 is a transforming growth factor beta (TGF-β) type I receptor predominantly expressed in actively proliferating endothelial cells (ECs). ALK1 has been shown to play a pivotal role in regulating angiogenesis by binding to bone morphogenetic protein (BMP)9 and 10. Two main pharmacological inhibitors, an ALK1-Fc fusion protein (Dalantercept/ACE-041) and a fully human antibody against the extracellular domain of ALK1 (PF-03446962) are currently under clinical development. Herein, we briefly recapitulate the role of ALK1 in blood vessel formation and the current status of the preclinical and clinical studies on inhibition of ALK1 signalling as an anti-angiogenic strategy. Future directions in terms of new combination regimens will also be presented.

scholarly journals The activin receptor-like kinase 6 Booroola mutation enhances suppressive effects of bone morphogenetic protein 2 (BMP2), BMP4, BMP6 and growth and differentiation factor-9 on FSH release from ovine primary pituitary cell cultures

2007 ◽  
Vol 196 (2) ◽  
pp. 251-261 ◽  
Author(s):  
Julia M Young ◽  
Jennifer L Juengel ◽  
Kenneth G Dodds ◽  
Mhairi Laird ◽  
Peter K Dearden ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Transforming Growth Factor ◽  
Direct Action ◽  
Pituitary Cell ◽  
Bone Morphogenetic Protein 2 ◽  
Pituitary Cells ◽  
Activin Receptor ◽  
Differentiation Factor ◽  
Receptor Like Kinase

Bone morphogenetic proteins (BMPs) have been shown to influence the regulation of FSH synthesis and secretion at the level of the pituitary. Primary pituitary cells were harvested and cultured from Booroola ewes homozygous for a mutation in activin receptor-like kinase 6 (ALK6) also known as BMP receptor IB (BMPRIB), and from wild-type (WT) ewes to determine if the mutation caused alterations in FSH secretion in vitro. The cells were collected 24 h following induction of luteolysis and cultured for 72 h prior to being challenged for 24 h with BMP2, BMP4, BMP6, growth and differentiation factor-9 (GDF9), transforming growth factor-β 1, activin-A and GnRH. The levels of FSH and LH were measured by RIA and then compared with the untreated controls. Primary pituitary cell cultures from Booroola ewes secreted less FSH than WT cells in the presence of BMP2, BMP4 and BMP6. These BMPs did not affect the FSH stores within the cells, or the levels of LH released. GDF9 appeared to act in a BMP-like manner by suppressing FSH secretion. The ALK6 receptor however, was not found to co-localise with gonadotroph cells in either Booroola or WT pituitary tissues. These findings imply that the increased sensitivity of Booroola cells to BMP2, BMP4, BMP6 and GDF9 cannot be due to the direct action of the ALK6 mutant Booroola receptor in the cells that synthesise FSH.

scholarly journals Selective inhibition of activin receptor-like kinase 5 signaling blocks profibrotic transforming growth factor ? responses in skin fibroblasts

2004 ◽  
Vol 50 (12) ◽  
pp. 4008-4021 ◽  
Author(s):  
Yasuji Mori ◽  
Wataru Ishida ◽  
Swati Bhattacharyya ◽  
Yongzhong Li ◽  
Leonidas C. Platanias ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Selective Inhibition ◽  
Skin Fibroblasts ◽  
Activin Receptor ◽  
Receptor Like Kinase

scholarly journals Up-and-down immunity of pregnancy in humans

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1216 ◽  
Author(s):  
Philippe Le Bouteiller ◽  
Armand Bensussan
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Embryo Implantation ◽  
Direct Interaction ◽  
Extravillous Trophoblast ◽  
Placental Development ◽  
Local Immunity ◽  
Healthy Pregnancy ◽  
Maternal Immune System ◽  
Decidual Cells

One part of the human placenta in early pregnancy is particularly important for local immunity: the decidua basalis, which is transformed endometrium located at the site of embryo implantation. This placental bed tissue contains both maternal uterine immune cells, including decidual natural killer (NK) cells, the dominant leukocyte population exhibiting a unique phenotype, and fetal extravillous trophoblast which comes into direct contact with maternal decidual cells. To establish a successful placental development and healthy pregnancy outcome, the maternal immune system must tolerate paternal antigens expressed by trophoblast cells yet remain efficient for clearing any local pathogen infection. This review deals mainly with decidual NK cells. A key element, among others, to achieve such dual functions is the direct interaction between activating and inhibitory receptors expressed by decidual NK cells and their specific ligands presented by trophoblast or other decidual cells. Depending whether maternal decidual cells and trophoblast are infected by viruses, the balance between activating and inhibitory receptor signals mediated by decidual NK cell–trophoblast cross-talk results in tolerance (healthy pregnancy) or specific killing (pathogen-infected cells).

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