DOCSLIB.ORG

Anti-Mullerian Hormone As a Marker of Oocyte Quantity, Developmental

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Anti-Mullerian Hormone As a Marker of Oocyte Quantity, Developmental Anti-Mullerian Hormone as a Marker of Oocyte Quantity, Developmental Potential, and Fetal Sex by Anja Stojsin Carter A Thesis Presented to The University of Guelph In partial fulfillment of requirements for the degree of Doctor of Philosophy in Biomedical Sciences Guelph, Ontario, Canada © Anja Stojsin Carter, December 2016 ABSTRACT ANTI-MULLERIAN HORMONE AS A MARKER OF OOCYTE QUANTITY, DEVELOPMENTAL POTENTIAL AND FETAL SEX Anja Stojsin Carter Advisor: University of Guelph, 2016 Professor W. A. King Delayed childbearing age, increased environmental pollutants accompanying modern life style, and an increase in inbreeding due to high demand for milk and meat yield have resulted in the decline in human and bovine reproduction respectively. Anti-Mullerian hormone (AMH) is expressed starting from 7-8 weeks of gestation in males and 20 weeks of gestation in females, in up to 100x higher concentration in males. AMH has been described as a non-invasive and accurate marker of ovarian quantitative fertility parameters in both humans and cattle. However, it is still unknown how AMH levels correlate to different fertility parameters in different cattle breeds; can AMH levels in the mother be used as a fetal sex marker during pregnancy in cows? In humans, can AMH collected in the single follicular fluid (mono FF), as well as granulosa cell (GC) AMH receptor 2 (AMHR2) be used as an embryo developmental potential marker? Here we present evidence of the higher levels of systemic and follicular AMH in Zebu compared to European cattle, corresponding to higher levels of AFC and oocytes. Cows pregnant with a male fetus, as compared to a female fetus, were observed to have a significantly different change in plasma AMH between day 35 and 135 during gestation. The placenta and cotyledon were found to express AMHR2 between day 38 and 80, however not significantly different between pregnancies with an opposite sex fetus. In the human study, systemic and average mono FF AMH, and average mono GC AMHR2 expression were significantly negatively correlated with the patient’s blastocyst rate. When patients were divided into normal and high groups based on the their systemic AMH levels, the following was observed: normal systemic AMH level patients had a lower average FF AMH level and a higher blastocyst rate compared to the higher systemic AMH level patients. Also, in normal systemic AMH patients, blastocysts corresponded to follicles with a lower level of AMH, while in high systemic AMH patients blastocysts corresponded to follicles with a higher level of AMH. iv DECLARATION OF WORK PERFORMED I declare that, with the exception of the items indicated below, all the work reported in the body of this thesis was performed by me. Cattle ovaries and reproductive tracts were collected by Pradeep Blaraju, Steven Huang, Heather Smale, Stephan Botha, and Brooklin Rushton during the course of these studies. Media used in Canada for oocyte in vitro maturation, in vitro fertilization, and in vitro culture were prepared by Liz St. John. Real time qPCR experiments in Chapter I were performed by Kiana Mahboubi. Cell culture and DNA extraction were performed by Dr. Olutobi Oluwole. Antral follicle count, ovary diameter measurements, serum collections, slaughterhouse ovary collection, bovine anti-Mullerian hormone ELISA measurements, and fetal serum collection in Brazil were performed with the help of Dr. Moyses Miranda, Dr. Otavio Ohashi, Dr. Nathalia Nogueira, Dr. Tiago de Bem, Rodrigo de Morais, Cinthia Lopes, Mayra Costa, Alessandra Ximenes, Tobias Sovernigo, and Marcus Filho. ONE Fertility patient consents were obtained by Melody Rasmussen and Maja Smrzlic. Human anti-Mullerian hormone ELISA measurements were performed by Alexandra Marinic-Cowden. Human follicular fluid collections were performed by Michael Neal. Human in vitro fertilization, culture, embryo assessment and transfer were performed by Katie Willoughby, Lisa Deys, and Lindsay Moffatt. Daniel Gillis performed most of the statistical analysis. v ACKNOWLEDGEMENTS First and foremost I would like to thank my supervisor Dr. Allan King. Allan provided me with the opportunity to work in his lab twice, doing a research project during the last year of my undergraduate degree, and then for my PhD, for which I was able to do a project highly relevant to my interests and goals. I was also given the opportunity to collaborate with a human fertility clinic and stay in close contact with the field in which my findings could have an impact. I also have to thank Allan for the opportunity to go on a research exchange to Brazil, to work with his collaborators in Belem, Para. Last but not least, Allan has been incredibly understanding of my personal life; I got married and had a baby after the second year of my degree. Allan organized the baby shower and allowed me to pursue motherhood in parallel with work on my thesis. The people Allan gathered around himself are all brilliant and I had the honor of being part of his team. I would like to thank Dr. Pavneesh Madan for his support throughout my project and his valuable input on the project progression and experiment planning. Dr. Madan also helped me troubleshoot through my immunofluorescence and confocal microscopy work, and was encouraging throughout my manuscript writing. I would like to thank Dr. Neil MacLusky for guidance and support during my committee meetings and for his help with some of my statistics questions. Neil is a very sweet, approachable and genuine person, finding time to talk to students and allowing them to feel like one of his colleagues. I would like to thank Mike Neal, ONE Fertility Burlington scientific director, for giving me the opportunity to collaborate, for his enthusiasm, for help with writing the ethics protocols, vi abstracts and manuscript, and for enabling me to collect valuable sample material, attend conferences, and extend my research opportunities by including a human study. I would like to thank Dr. Julang Li, my external committee member, for kind words, support and guidance. I would like to give a special Thank You to Dr. Laura Favetta. Dr. Favetta was my advisor, my friend, my sister, my parent. I met Laura during my undergraduate degree project and she has provided me with infinite help since then. It was an honor knowing Dr. Favetta, with her devoted and passionate approach to students and teaching. Dr. Favetta’s knowledge on qPCR and endocrinology kept me going in the right direction! I would like to thank Dr. Daniel Gillis for his immense help and patience in performing majority of the statistical analysis in this thesis. I would like to thank Liz St. John for her help with ovary and placenta collections, support in any lab related issues, and who, with her kindness, never intimidated the students around her. I would like to thank Dr. Monica Antenos for sharing her knowledge, and providing incredible support in the lab, where she created a friendly, relaxed, but very stimulating atmosphere. I would like to thank Ed Reyes and Allison MacKay for their technical support and patience, dealing with ordering supplies and questions at, often, inconvenient times. I would like to thank Helen Coates for her patience and help with confocal microcopy. I would like to thank Dr. Tamas Ravay for his valuable input in qPCR and immunofluorescence and molecular troubleshooting. Dr. Ravay was also more than just a colleague; he was a friend and a support throughout this project. vii I would like to thank Kiana Mahboube, a Masters student, who worked on part of my project and helped incredibly with qPCR work, and who has also been a close friend and support. I would like to thank to Dr. Stalker, Kata Ozs, and Dr. Petrik for their help with troubleshooting experiments and cell material. I would also like to thank our collaborators and extended family in Brazil, Dr. Miranda, Dr. Ohashi, Dr. Costa, Dr. de Bem, and many others. Without your input this project would have been so much more boring. I loved my experience in Brazil, and thank you for providing me with so many opportunities to examine and learn so much about your beautiful cattle: Bos taurus indicus. I would also like to extend my gratitude to the team at ONE Fertility, Burlington. Thank you to the embryologists: Katie, Lindsay, and Lisa for their patience to have me in the lab during their busy schedules, to have patients answer my questions, and to trust me to help them with some of their media preparations and case setups. I also would like to thank the andrology team: Tiffany and Leanne for allowing me to use some of their space to prepare research samples. I would like to thank the staff: Melody, Maja and Alexandra for their help with patient consent forms and running the human ELISA. Last but not least, I would like to thank Dr. Karnis, Dr. Amin, Dr. Huges and Dr. Faghih for their trust and the opportunity to collaborate. This research would have not been possible without the financial support from the OVC Doctoral Scholarship, The Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Research Chair (CRC), and North/South Animal Biology and Reproductive Biotechnology Consortium- Canada/Brazil Doctoral Student Research Exchange. viii I would now like to thank my friends and family all around the world. I would like to thank my friends in Canada: Carolyn, Sarah, Jacky, Tobi, Kayla, Allison, Carmon, Leslie, Stewart, Graham, Faz, Anh, Nayoung, Jyoti, Nina, Anuja, Moez, Ari and many others in the Biomedical Sciences Department, including staff Kim Best and Frances Graziotto, for their friendship and support. I would like to thank especially my friend Gilan Abdelaal, who was there for me through the good, bad and the ugly. I would like to thank my former high school teacher Dragan Gajic, for his love and passion for science that molded my undergrad and grad scientific path.
Load more

Recommended publications
  • Spemann Organizer Transcriptome Induction by Early Beta-Catenin, Wnt
    Spemann organizer transcriptome induction by early PNAS PLUS beta-catenin, Wnt, Nodal, and Siamois signals in Xenopus laevis Yi Dinga,b,1, Diego Plopera,b,1, Eric A. Sosaa,b, Gabriele Colozzaa,b, Yuki Moriyamaa,b, Maria D. J. Beniteza,b, Kelvin Zhanga,b, Daria Merkurjevc,d,e, and Edward M. De Robertisa,b,2 aHoward Hughes Medical Institute, University of California, Los Angeles, CA 90095-1662; bDepartment of Biological Chemistry, University of California, Los Angeles, CA 90095-1662; cDepartment of Medicine, University of California, Los Angeles, CA 90095-1662; dDepartment of Microbiology, University of California, Los Angeles, CA 90095-1662; and eDepartment of Human Genetics, University of California, Los Angeles, CA 90095-1662 Contributed by Edward M. De Robertis, February 24, 2017 (sent for review January 17, 2017; reviewed by Juan Larraín and Stefano Piccolo) The earliest event in Xenopus development is the dorsal accumu- Wnt8 mRNA leads to a dorsalized phenotype consisting entirely of lation of nuclear β-catenin under the influence of cytoplasmic de- head structures without trunks and a radial Spemann organizer terminants displaced by fertilization. In this study, a genome-wide (9–11). Similar dorsalizing effects are obtained by incubating approach was used to examine transcription of the 43,673 genes embryos in lithium chloride (LiCl) solution at the 32-cell stage annotated in the Xenopus laevis genome under a variety of con- (12). LiCl mimics the early Wnt signal by inhibiting the enzymatic ditions that inhibit or promote formation of the Spemann orga- activity of glycogen synthase kinase 3 (GSK3) (13), an enzyme nizer signaling center.
    [Show full text]
  • Follistatin and Noggin Are Excluded from the Zebrafish Organizer
    DEVELOPMENTAL BIOLOGY 204, 488–507 (1998) ARTICLE NO. DB989003 Follistatin and Noggin Are Excluded from the Zebrafish Organizer Hermann Bauer,* Andrea Meier,* Marc Hild,* Scott Stachel,†,1 Aris Economides,‡ Dennis Hazelett,† Richard M. Harland,† and Matthias Hammerschmidt*,2 *Max-Planck Institut fu¨r Immunbiologie, Stu¨beweg 51, 79108 Freiburg, Germany; †Department of Molecular and Cell Biology, University of California, 401 Barker Hall 3204, Berkeley, California 94720-3204; and ‡Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591-6707 The patterning activity of the Spemann organizer in early amphibian embryos has been characterized by a number of organizer-specific secreted proteins including Chordin, Noggin, and Follistatin, which all share the same inductive properties. They can neuralize ectoderm and dorsalize ventral mesoderm by blocking the ventralizing signals Bmp2 and Bmp4. In the zebrafish, null mutations in the chordin gene, named chordino, lead to a severe reduction of organizer activity, indicating that Chordino is an essential, but not the only, inductive signal generated by the zebrafish organizer. A second gene required for zebrafish organizer function is mercedes, but the molecular nature of its product is not known as yet. To investigate whether and how Follistatin and Noggin are involved in dorsoventral (D-V) patterning of the zebrafish embryo, we have now isolated and characterized their zebrafish homologues. Overexpression studies demonstrate that both proteins have the same dorsalizing properties as their Xenopus homologues. However, unlike the Xenopus genes, zebrafish follistatin and noggin are not expressed in the organizer region, nor are they linked to the mercedes mutation. Expression of both genes starts at midgastrula stages.
    [Show full text]
  • Nodal Signaling Is Required for Mesodermal and Ventral but Not For
    © 2015. Published by The Company of Biologists Ltd | Biology Open (2015) 4, 830-842 doi:10.1242/bio.011809 RESEARCH ARTICLE Nodal signaling is required for mesodermal and ventral but not for dorsal fates in the indirect developing hemichordate, Ptychodera flava Eric Röttinger1,2,3,*, Timothy Q. DuBuc4, Aldine R. Amiel1,2,3 and Mark Q. Martindale4 ABSTRACT early fate maps of direct and indirect developing hemichordates, are Nodal signaling plays crucial roles in vertebrate developmental similar to those of indirect-developing echinoids (Colwin and processes such as endoderm and mesoderm formation, and axial Colwin, 1951; Cameron et al., 1987; Cameron et al., 1989; Cameron patterning events along the anteroposterior, dorsoventral and left- and Davidson, 1991; Henry et al., 2001). While the bilaterally right axes. In echinoderms, Nodal plays an essential role in the symmetric echinoderm larvae exhibit strong similarities to establishment of the dorsoventral axis and left-right asymmetry, but chordates in axial patterning and germ layer specification events, not in endoderm or mesoderm induction. In protostomes, Nodal adult body plan comparisons in echinoderms have been difficult due signaling appears to be involved only in establishing left-right to their unique adult pentaradial symmetry. However, both the larval asymmetry. Hence, it is hypothesized that Nodal signaling has and adult body plans of enteropneust hemichordates are bilaterally been co-opted to pattern the dorsoventral axis of deuterostomes and symmetric, and larvae from indirect developing hemichordates for endoderm, mesoderm formation as well as anteroposterior such as Ptychodera flava (P. flava) share similarities in patterning in chordates. Hemichordata, together with echinoderms, morphology, axial organization, and developmental fate map with represent the sister taxon to chordates.
    [Show full text]
  • Inhibition of Activin/Nodal and Wnt Signaling Andrey V
    RESEARCH ARTICLE 5345 Development 138, 5345-5356 (2011) doi:10.1242/dev.068908 © 2011. Published by The Company of Biologists Ltd Novel functions of Noggin proteins: inhibition of Activin/Nodal and Wnt signaling Andrey V. Bayramov*, Fedor M. Eroshkin*, Natalia Y. Martynova, Galina V. Ermakova, Elena A. Solovieva and Andrey G. Zaraisky‡ SUMMARY The secreted protein Noggin1 is an embryonic inducer that can sequester TGF cytokines of the BMP family with extremely high affinity. Owing to this function, ectopic Noggin1 can induce formation of the headless secondary body axis in Xenopus embryos. Here, we show that Noggin1 and its homolog Noggin2 can also bind, albeit less effectively, to ActivinB, Nodal/Xnrs and XWnt8, inactivation of which, together with BMP, is essential for the head induction. In support of this, we show that both Noggin proteins, if ectopically produced in sufficient concentrations in Xenopus embryo, can induce a secondary head, including the forebrain. During normal development, however, Noggin1 mRNA is translated in the presumptive forebrain with low efficiency, which provides the sufficient protein concentration for only its BMP-antagonizing function. By contrast, Noggin2, which is produced in cells of the anterior margin of the neural plate at a higher concentration, also protects the developing forebrain from inhibition by ActivinB and XWnt8 signaling. Thus, besides revealing of novel functions of Noggin proteins, our findings demonstrate that specification of the forebrain requires isolation of its cells from BMP, Activin/Nodal and Wnt signaling not only during gastrulation but also at post-gastrulation stages. KEY WORDS: Noggin, Activin, Nodal, Wnt, Forebrain, Xenopus INTRODUCTION laevis embryos, to bind to and antagonize several secreted proteins The secreted protein Noggin (Noggin1) was first discovered in known to be involved in regulation of TGF and Wnt signaling.
    [Show full text]
  • Signal Transduction Pathway Through Activin Receptors As a Therapeutic Target of Musculoskeletal Diseases and Cancer
    Endocr. J./ K. TSUCHIDA et al.: SIGNALING THROUGH ACTIVIN RECEPTORS doi: 10.1507/endocrj.KR-110 REVIEW Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer KUNIHIRO TSUCHIDA, MASASHI NAKATANI, AKIYOSHI UEZUMI, TATSUYA MURAKAMI AND XUELING CUI Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan Received July 6, 2007; Accepted July 12, 2007; Released online September 14, 2007 Correspondence to: Kunihiro TSUCHIDA, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan Abstract. Activin, myostatin and other members of the TGF-β superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of activins and nodal, activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-β, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and three type I receptors, ALK2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors.
    [Show full text]
  • Supplementary Materials
    Supplementary Materials + - NUMB E2F2 PCBP2 CDKN1B MTOR AKT3 HOXA9 HNRNPA1 HNRNPA2B1 HNRNPA2B1 HNRNPK HNRNPA3 PCBP2 AICDA FLT3 SLAMF1 BIC CD34 TAL1 SPI1 GATA1 CD48 PIK3CG RUNX1 PIK3CD SLAMF1 CDKN2B CDKN2A CD34 RUNX1 E2F3 KMT2A RUNX1 T MIXL1 +++ +++ ++++ ++++ +++ 0 0 0 0 hematopoietic potential H1 H1 PB7 PB6 PB6 PB6.1 PB6.1 PB12.1 PB12.1 Figure S1. Unsupervised hierarchical clustering of hPSC-derived EBs according to the mRNA expression of hematopoietic lineage genes (microarray analysis). Hematopoietic-competent cells (H1, PB6.1, PB7) were separated from hematopoietic-deficient ones (PB6, PB12.1). In this experiment, all hPSCs were tested in duplicate, except PB7. Genes under-expressed or over-expressed in blood-deficient hPSCs are indicated in blue and red respectively (related to Table S1). 1 C) Mesoderm B) Endoderm + - KDR HAND1 GATA6 MEF2C DKK1 MSX1 GATA4 WNT3A GATA4 COL2A1 HNF1B ZFPM2 A) Ectoderm GATA4 GATA4 GSC GATA4 T ISL1 NCAM1 FOXH1 NCAM1 MESP1 CER1 WNT3A MIXL1 GATA4 PAX6 CDX2 T PAX6 SOX17 HBB NES GATA6 WT1 SOX1 FN1 ACTC1 ZIC1 FOXA2 MYF5 ZIC1 CXCR4 TBX5 PAX6 NCAM1 TBX20 PAX6 KRT18 DDX4 TUBB3 EPCAM TBX5 SOX2 KRT18 NKX2-5 NES AFP COL1A1 +++ +++ 0 0 0 0 ++++ +++ ++++ +++ +++ ++++ +++ ++++ 0 0 0 0 +++ +++ ++++ +++ ++++ 0 0 0 0 hematopoietic potential H1 H1 H1 H1 H1 H1 PB6 PB6 PB7 PB7 PB6 PB6 PB7 PB6 PB6 PB6.1 PB6.1 PB6.1 PB6.1 PB6.1 PB6.1 PB12.1 PB12.1 PB12.1 PB12.1 PB12.1 PB12.1 Figure S2. Unsupervised hierarchical clustering of hPSC-derived EBs according to the mRNA expression of germ layer differentiation genes (microarray analysis) Selected ectoderm (A), endoderm (B) and mesoderm (C) related genes differentially expressed between hematopoietic-competent (H1, PB6.1, PB7) and -deficient cells (PB6, PB12.1) are shown (related to Table S1).
    [Show full text]
  • Vg1-Nodal Heterodimers Are the Endogenous Inducers of Mesendoderm Tessa G Montague1*, Alexander F Schier1,2,3,4,5*
    RESEARCH ARTICLE Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm Tessa G Montague1*, Alexander F Schier1,2,3,4,5* 1Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States; 2Center for Brain Science, Harvard University, Cambridge, United States; 3Broad Institute of MIT and Harvard, Cambridge, United States; 4Harvard Stem Cell Institute, Cambridge, United States; 5FAS Center for Systems Biology, Harvard University, Cambridge, United States Abstract Nodal is considered the key inducer of mesendoderm in vertebrate embryos and embryonic stem cells. Other TGF-beta-related signals, such as Vg1/Dvr1/Gdf3, have also been implicated in this process but their roles have been unclear or controversial. Here we report that zebrafish embryos without maternally provided vg1 fail to form endoderm and head and trunk mesoderm, and closely resemble nodal loss-of-function mutants. Although Nodal is processed and secreted without Vg1, it requires Vg1 for its endogenous activity. Conversely, Vg1 is unprocessed and resides in the endoplasmic reticulum without Nodal, and is only secreted, processed and active in the presence of Nodal. Co-expression of Nodal and Vg1 results in heterodimer formation and mesendoderm induction. Thus, mesendoderm induction relies on the combination of two TGF-beta- related signals: maternal and ubiquitous Vg1, and zygotic and localized Nodal. Modeling reveals that the pool of maternal Vg1 enables rapid signaling at low concentrations of zygotic Nodal. DOI: https://doi.org/10.7554/eLife.28183.001 Introduction *For correspondence: tessa. [email protected] (TGM); The induction of mesoderm and endoderm (mesendoderm) during embryogenesis and embryonic [email protected] (AFS) stem cell differentiation generates the precursors of the heart, liver, gut, pancreas, kidney and other internal organs.
    [Show full text]
  • Activin/Nodal Signalling in Stem Cells Siim Pauklin and Ludovic Vallier*
    © 2015. Published by The Company of Biologists Ltd | Development (2015) 142, 607-619 doi:10.1242/dev.091769 REVIEW Activin/Nodal signalling in stem cells Siim Pauklin and Ludovic Vallier* ABSTRACT organisms. Of particular relevance, genetic studies in the mouse Activin/Nodal growth factors control a broad range of biological have established that Nodal signalling is necessary at the early processes, including early cell fate decisions, organogenesis and epiblast stage during implantation, in which the pathway functions adult tissue homeostasis. Here, we provide an overview of the to maintain the expression of key pluripotency factors as well as to mechanisms by which the Activin/Nodal signalling pathway governs regulate the differentiation of extra-embryonic tissue. Activins, β stem cell function in these different stages of development. dimers of different subtypes of Inhibin , are also expressed in pre- We describe recent findings that associate Activin/Nodal signalling implantation blastocyst but not in the primitive streak (Albano to pathological conditions, focusing on cancer stem cells in et al., 1993; Feijen et al., 1994). However, genetic studies have β tumorigenesis and its potential as a target for therapies. Moreover, shown that Inhibin s are not necessary for early development in the we will discuss future directions and questions that currently remain mouse (Lau et al., 2000; Matzuk, 1995; Matzuk et al., 1995a,b). unanswered on the role of Activin/Nodal signalling in stem cell self- Combined gradients of Nodal and BMP signalling within the renewal, differentiation and proliferation. primitive streak control endoderm and mesoderm germ layer specification and also their subsequent patterning whilst blocking KEY WORDS: Activin, Cell cycle, Differentiation, Nodal, neuroectoderm formation (Camus et al., 2006; Mesnard et al., Pluripotency, Stem cells 2006).
    [Show full text]
  • Nodal Facilitates Differentiation of Fibroblasts to Cancer-Associated
    cells Article Nodal Facilitates Differentiation of Fibroblasts to Cancer-Associated Fibroblasts that Support Tumor Growth in Melanoma and Colorectal Cancer Ziqian Li 1, Junjie Zhang 1, Jiawang Zhou 1, Linlin Lu 1, Hongsheng Wang 1, Ge Zhang 1, Guohui Wan 1, Shaohui Cai 2 and Jun Du 1,* 1 Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; [email protected] (Z.L.); [email protected] (J.Z.); [email protected] (J.Z.); [email protected] (L.L.); [email protected] (H.W.); [email protected] (G.Z.); [email protected] (G.W.) 2 Department of Pharmacology, School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China; [email protected] * Correspondence: [email protected]; Tel.: +86-20-3994-3022; Fax: +86-20-3994-3022 Received: 15 May 2019; Accepted: 3 June 2019; Published: 4 June 2019 Abstract: Fibroblasts become cancer-associated fibroblasts (CAFs) in the tumor microenvironment after activation by transforming growth factor-β (TGF-β) and are critically involved in cancer progression. However, it is unknown whether the TGF superfamily member Nodal, which is expressed in various tumors but not expressed in normal adult tissue, influences the fibroblast to CAF conversion. Here, we report that Nodal has a positive correlation with α-smooth muscle actin (α-SMA) in clinical melanoma and colorectal cancer (CRC) tissues. We show the Nodal converts normal fibroblasts to CAFs, together with Snail and TGF-β signaling pathway activation in fibroblasts. Activated CAFs promote cancer growth in vitro and tumor-bearing mouse models in vivo.
    [Show full text]
  • Coordinate Regulation of Cell Growth and Differentiation by TGF-B Superfamily and Runx Proteins
    Oncogene (2004) 23, 4232–4237 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc Coordinate regulation of cell growth and differentiation by TGF-b superfamily and Runx proteins Kohei Miyazono*,1,2, Shingo Maeda2 and Takeshi Imamura2 1Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; 2Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan Runx proteins regulate various biological processes, of cells, including epithelial cells, endothelial cells, including growth and differentiation of hematopoietic hematopoietic cells, and lymphocytes.Perturbations cells, lymphocytes, osteoblasts, and gastric epithelial cells. of TGF-b signaling therefore result in progression of Some of the biological activities of Runx proteins are some tumors (Derynck et al., 2001; Wakefield and reminiscent of those of transforming growth factor Roberts, 2002).However, TGF- b stimulates growth of (TGF)-b superfamily cytokines. Consistent with this certain types of cells, including mesenchymal cells, notion, receptor-regulated Smads (R-Smads), signal and induces epithelial-to-mesenchymal transdifferen- mediators of the TGF-b superfamily cytokines, and Runx tiation (EMT) of some epithelial cells.Moreover, proteins have been shown to physically interact with each TGF-b stimulates extracellular matrix accumulation, other. R-Smads activated by TGF-b and Runx proteins angiogenesis, immunosuppression, and secretion of cooperatively induce synthesis of IgA in B lymphocytes, parathyroid hormone-related peptide (PTHrP).TGF- b and those activated by bone morphogenetic proteins and may thus function as a pro-oncogenic cytokine Runx2 induce osteoblastic differentiation.
    [Show full text]
  • Follistatin Is Critical for Mouse Uterine Receptivity and Decidualization
    Follistatin is critical for mouse uterine receptivity PNAS PLUS and decidualization Paul T. Fullerton Jr.a,b,c,d, Diana Monsivaisa,c,d, Ramakrishna Kommaganie, and Martin M. Matzuka,b,c,d,e,f,1 aDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; bDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; cCenter for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030; dCenter for Drug Discovery, Baylor College of Medicine, Houston, TX 77030; eDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; and fDepartment of Pharmacology, Baylor College of Medicine, Houston, TX 77030 Contributed by Martin M. Matzuk, April 26, 2017 (sent for review December 19, 2016; reviewed by Kate L. Loveland and Felice Petraglia) Embryo implantation remains a significant challenge for assisted predominant form found in circulation. In humans, aberrant ex- reproductive technology, with implantation failure occurring in pression of FST and activins are implicated in infertility; dysregu- ∼50% of in vitro fertilization attempts. Understanding the molecular lation of FST, activins, and inhibins was reported in women with mechanisms underlying uterine receptivity will enable the develop- impending abortion (10), recurrent miscarriage (11, 12), hyperten- ment of new interventions and biomarkers. TGFβ family signaling in sive disorders during pregnancy (13), and repeated implantation the uterus is critical for establishing and maintaining pregnancy. Fol- failure after in vitro fertilization (14). However, the role that FST listatin (FST) regulates TGFβ family signaling by selectively binding plays in normal pregnancy remains uncertain. TGFβ family ligands and sequestering them. In humans, FST is up- FST knockout is perinatal lethal in mice (15), precluding study of regulated in the decidua during early pregnancy, and women with its role in reproduction with a global inactivation.
    [Show full text]
  • The Role of Bone Morphogenetic Protein 7 (BMP-7) in Inflammation in Heart Diseases
    cells Review The Role of Bone Morphogenetic Protein 7 (BMP-7) in Inflammation in Heart Diseases Chandrakala Aluganti Narasimhulu and Dinender K Singla * Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-407-823-0953; Fax: +1-407-823-0956 Received: 2 January 2020; Accepted: 21 January 2020; Published: 23 January 2020 Abstract: Bone morphogenetic protein-7 is (BMP-7) is a potent anti-inflammatory growth factor belonging to the Transforming Growth Factor Beta (TGF-β) superfamily. It plays an important role in various biological processes, including embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis. BMP-7 stimulates the target cells by binding to specific membrane-bound receptor BMPR 2 and transduces signals through mothers against decapentaplegic (Smads) and mitogen activated protein kinase (MAPK) pathways. To date, rhBMP-7 has been used clinically to induce the differentiation of mesenchymal stem cells bordering the bone fracture site into chondrocytes, osteoclasts, the formation of new bone via calcium deposition and to stimulate the repair of bone fracture. However, its use in cardiovascular diseases, such as atherosclerosis, myocardial infarction, and diabetic cardiomyopathy is currently being explored. More importantly, these cardiovascular diseases are associated with inflammation and infiltrated monocytes where BMP-7 has been demonstrated to be a key player in the differentiation of pro-inflammatory monocytes, or M1 macrophages, into anti-inflammatory M2 macrophages, which reduces developed cardiac dysfunction. Therefore, this review focuses on the molecular mechanisms of BMP-7 treatment in cardiovascular disease and its role as an anti-fibrotic, anti-apoptotic and anti-inflammatory growth factor, which emphasizes its potential therapeutic significance in heart diseases.
    [Show full text]