scholarly journals MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation

2018 ◽  
Vol 50 (1) ◽  
pp. 10-19 ◽  
Author(s):  
Lucy Li ◽  
Lewis P. Rubin ◽  
Xiaoming Gong
Keyword(s):  
Transcription Factors ◽  
Human Placenta ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Dominant Negative ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Cytotrophoblast Cell ◽  
Adverse Pregnancy

Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.

scholarly journals Modelling the Human Placental Interface In Vitro—A Review

Micromachines ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 884
Author(s):  
Marta Cherubini ◽  
Scott Erickson ◽  
Kristina Haase
Keyword(s):  
Drug Testing ◽  
Cell Types ◽  
In Vitro Models ◽  
Placental Development ◽  
Scientific Challenge ◽  
Induced Pluripotent ◽  
And Function ◽  
And Control

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal–fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

Developmental expression of the maternal protein XDCoH, the dimerization cofactor of the homeoprotein LFB1 (HNF1)

Development ◽  
1995 ◽  
Vol 121 (4) ◽  
pp. 1217-1226
Author(s):  
E. Pogge yon Strandmann ◽  
G.U. Ryffel
Keyword(s):  
Transcription Factors ◽  
Anterior Part ◽  
Regulatory Element ◽  
Cdna Probe ◽  
Cell Types ◽  
Developmental Expression ◽  
Variant Form ◽  
Cis Acting ◽  
Liver And Kidney

The tissue-specific transcription factors LFB1 (HNF1) and LFB3 (vHNF1) mainly expressed in liver, kidney and intestine are homeoproteins that interact with the regulatory element HP1. The HP1 sequence constitutes one of the most important cis-acting elements in liver-specifically expressed genes, while its function in other cell types containing LFB1 and LFB3 is not fully understood. In mammals, LFB1 activity is modulated by DCoH, a cofactor that stimulates the LFB1 transactivation significantly. Using the rat cDNA probe, we cloned the corresponding Xenopus sequence XDCoH, encoding a 104 amino acid protein, that is 85% identical to the rat protein. XDCoH enhances the LFB1-dependent transactivation potential in transfection experiments and interacts in vitro directly with LFB1 and its variant form LFB3. The protein is detectable in liver and kidney extracts of adult frogs and in small amounts also in lung and stomach, organs expressing LFB1 and/or LFB3 protein as well. To investigate the possible involvement of XDCoH in Xenopus development, we analyzed its temporal and spatial expression pattern during early embryogenesis. XDCoH is a maternal factor, although LFB1 is absent in the egg. In early cleavage stages, the protein is detectable in the cytoplasm of each blastomere and enters the nuclei of the cells as early as the zygotic transcription in the Xenopus embryo starts. The amount of XDCoH increases dramatically following neurulation, when the formation of liver, pronephros and other organs takes place. Whole-mount immunostaining demonstrates that, in the developing larvae, XDCoH is localized in the nuclei of the hepatocytes, the gut cells and the pronephric cells, tissues of mesodermal and endodermal origin known to contain LFB1 and LFB3. Surprisingly it is also present in the pigmented epithelium surrounding the eye of the embryo, which is derived from the anterior part of the ectodermal neural plates and lacks LFB1. The tissue distribution of XDCoH during embryogenesis suggests that XDCoH is involved in determination and differentiation of various unrelated cell types. It seems likely that XDCoH interaction is not only essential for the function of LFB1 and LFB3 but also for certain other transcription factors.

scholarly journals Antigen-stimulated Activation of Phospholipase D1b by Rac1, ARF6, and PKCα in RBL-2H3 Cells

2002 ◽  
Vol 13 (4) ◽  
pp. 1252-1262 ◽  
Author(s):  
Dale J. Powner ◽  
Matthew N. Hodgkin ◽  
Michael J.O. Wakelam
Keyword(s):  
Plasma Membrane ◽  
Cell Types ◽  
Enzyme Activation ◽  
Dominant Negative ◽  
Ph Domain ◽  
Phosphatidylinositol 3 Kinase ◽  
Stimulation Of ◽  
Phosphatidylinositol 3

Phospholipase D (PLD) activity can be detected in response to many agonists in most cell types; however, the pathway from receptor occupation to enzyme activation remains unclear. In vitro PLD1b activity is phosphatidylinositol 4,5-bisphosphate dependent via an N-terminal PH domain and is stimulated by Rho, ARF, and PKC family proteins, combinations of which cooperatively increase this activity. Here we provide the first evidence for the in vivo regulation of PLD1b at the molecular level. Antigen stimulation of RBL-2H3 cells induces the colocalization of PLD1b with Rac1, ARF6, and PKCα at the plasma membrane in actin-rich structures, simultaneously with cooperatively increasing PLD activity. Activation is both specific and direct because dominant negative mutants of Rac1 and ARF6 inhibit stimulated PLD activity, and surface plasmon resonance reveals that the regulatory proteins bind directly and independently to PLD1b. This also indicates that PLD1b can concurrently interact with a member from each regulator family. Our results show that in contrast to PLD1b's translocation to the plasma membrane, PLD activation is phosphatidylinositol 3-kinase dependent. Therefore, because inactive, dominant negative GTPases do not activate PLD1b, we propose that activation results from phosphatidylinositol 3-kinase–dependent stimulation of Rac1, ARF6, and PKCα.

scholarly journals Poorly controlled diabetes mellitus alters placental structure, efficiency, and plasticity

2020 ◽  
Vol 8 (1) ◽  
pp. e001243
Author(s):  
Jackson Nteeba ◽  
Kaela M Varberg ◽  
Regan L Scott ◽  
Mikaela E Simon ◽  
Khursheed Iqbal ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Fetal Development ◽  
Trophoblast Invasion ◽  
Ambient Conditions ◽  
Placental Development ◽  
Junctional Zone ◽  
Pregnant Rat ◽  
Elevated Glucose ◽  
The Impact

IntroductionThe hemochorial placenta provides a critical barrier at the maternal–fetal interface to modulate maternal immune tolerance and enable gas and nutrient exchange between mother and conceptus. Pregnancy outcomes are adversely affected by diabetes mellitus; however, the effects of poorly controlled diabetes on placental formation, and subsequently fetal development, are not fully understood.Research design and methodsStreptozotocin was used to induce hyperglycemia in pregnant rats for the purpose of investigating the impact of poorly controlled diabetes on placental formation and fetal development. The experimental paradigm of hypoxia exposure in the pregnant rat was also used to assess properties of placental plasticity. Euglycemic and hyperglycemic rats were exposed to ambient conditions (~21% oxygen) or hypoxia (10.5% oxygen) beginning on gestation day (gd) 6.5 and sacrificed on gd 13.5. To determine whether the interaction of hyperglycemia and hypoxia was directly altering trophoblast lineage development, rat trophoblast stem (TS) cells were cultured in high glucose (25 mM) and/or exposed to low oxygen (0.5% to 1.5%).ResultsDiabetes caused placentomegaly and placental malformation, decreasing placental efficiency and fetal size. Elevated glucose disrupted rat TS cell differentiation in vitro. Evidence of altered trophoblast differentiation was also observed in vivo, as hyperglycemia affected the junctional zone transcriptome and interfered with intrauterine trophoblast invasion and uterine spiral artery remodeling. When exposed to hypoxia, hyperglycemic rats showed decreased proliferation and ectoplacental cone development on gd 9.5 and complete pregnancy loss by gd 13.5. Furthermore, elevated glucose concentrations inhibited TS cell responses to hypoxia in vitro.ConclusionsOverall, these results indicate that alterations in placental development, efficiency, and plasticity could contribute to the suboptimal fetal outcomes in offspring from pregnancies complicated by poorly controlled diabetes.

Recreating a Human Hematopoietic Stem Cell Niche in Vitro by Unique Stroma Cells from the First Trimester Human Placenta and Fetal Liver

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3568-3568
Author(s):  
Mattias Magnusson ◽  
Melissa Romero ◽  
Sacha Prashad ◽  
Ben Van Handel ◽  
Suvi Aivio ◽  
...  
Keyword(s):  
Stem Cells ◽  
Human Placenta ◽  
Ex Vivo ◽  
Fetal Liver ◽  
Embryonic Stem ◽  
Cell Types ◽  
First Trimester ◽  
Hematopoietic Stem ◽  
Human Hscs

Abstract Expansion of human hematopoietic stem cells (HSCs) ex vivo has been difficult due to limited understanding of their growth requirements and the molecular complexity of their natural microenvironments. To mimic the niches in which human HSCs normally develop and expand during ontogeny, we have derived two unique types of stromal niche cells from the first trimester human placenta and the fetal liver. These lines either support maintenance of multipotential progenitors in culture, or promote differentiation into macrophages. Impressively, the supportive lines facilitate over 50,000-fold expansion of the most immature human HSCs/progenitors (CD34+CD38-Thy1+) during 8-week culture supplemented with minimal cytokines FLT3L, SCF and TPO, whereas the cells cultured on non-supportive stroma or without stroma under the same conditions differentiated within 2 weeks. As the supportive stroma lines also facilitate differentiation of human hematopoietic progenitors into myeloid, erythroid and B-lymphoid lineages, we were able to show that the expanded progenitors preserved full multipotentiality during long-term culture ex vivo. Furthermore, our findings indicate that the supportive stroma lines also direct differentiation of human embryonic stem cells (hESC) into hematopoietic progenitor cells (CD45+CD34+) that generate multiple types of myeloerythroid colonies. These data imply that the unique supportive niche cells can both support hematopoietic specification and sustain a multilineage hematopoietic hierarchy in culture over several weeks. Strikingly, the supportive effect from the unique stromal cells was dominant over the differentiation effect from the non-supportive lines. Even supernatant from the supportive lines was able to partially protect the progenitors that were cultured on the non-supportive lines, whereas mixing of the two types of stroma resulted in sustained preservation of the multipotential progenitors. These results indicate that the supportive stroma cells possess both secreted and surface bound molecules that protect multipotentiality of HSCs. Global gene expression analysis revealed that the supportive stroma lines from both the placenta and the fetal liver were almost identical (r=0.99) and very different from the non-supportive lines that promote differentiation (r=0.34), implying that they represent two distinct niche cell types. Interestingly, the non-supportive lines express known mesenchymal markers such as (CD73, CD44 and CD166), whereas the identity of the supportive cells is less obvious. In summary, we have identified unique human stromal niche cells that may be critical components of the HSC niches in the placenta and the fetal liver. Molecular characterization of these stroma lines may enable us to define key mechanisms that govern the multipotentiality of HSCs.

scholarly journals Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation.

1993 ◽  
Vol 13 (2) ◽  
pp. 841-851 ◽  
Author(s):  
K A Lord ◽  
A Abdollahi ◽  
B Hoffman-Liebermann ◽  
D A Liebermann
Keyword(s):  
Transcription Factors ◽  
Leucine Zipper ◽  
Culture Media ◽  
Terminal Differentiation ◽  
Cell Types ◽  
Primary Response ◽  
Myeloid Differentiation ◽  
Active Transcription

The proto-oncogenes c-jun, junB, junD, and c-fos recently have been shown to encode for transcription factors with a leucine zipper that mediates dimerization to constitute active transcription factors; juns were shown to dimerize with each other and with c-fos, whereas fos was shown to dimerize only with juns. After birth, hematopoietic cells of the myeloid lineage, and some other terminally differentiated cell types, express high levels of c-fos. Still, the role of fos/jun transcription factors in normal myelopoiesis or in leukemogenesis has not been established. Recently, c-jun, junB, and junD were identified as myeloid differentiation primary response genes stably expressed following induction of terminal differentiation of myeloblastic leukemia M1 cells. Intriguingly, c-fos, though induced during normal myelopoiesis, was not induced upon M1 differentiation. To gain further insights into the role of fos/jun in normal myelopoiesis and leukemogenicity, M1fos and M1junB cell lines, which constitutively express c-fos and junB, respectively, were established. It was shown that enforced expression of c-fos, and to a lesser extent junB, in M1 cells results in both an increased propensity to differentiate and a reduction in the aggressiveness of the M1 leukemic phenotype. M1fos cells constitutively expressed immediate-early and late genetic markers of differentiated M1 cells. The in vitro differentiation of normal myeloblasts into mature macrophages and granulocytes, as well as the increased propensity of M1fos leukemic myeloblasts to be induced for terminal differentiation, was dramatically impaired with use of c-fos antisense oligomers in the culture media. Taken together, these observations show that the proto-oncogenes which encode for fos/jun transcription factors play important roles in promoting myeloid differentiation. The ability of the M1 leukemic myeloblasts to be induced for terminal differentiation in the absence of apparent fos expression indicates that there is some redundancy among the fos/jun family of transcription factors in promoting myeloid differentiation; however, juns alone cannot completely compensate for the lack of fos. Thus, genetic lesions affecting fos/jun expression may play a role in the development of "preleukemic" myelodysplastic syndromes and their further progression to leukemias.

scholarly journals 52GREATER PHENOTYPIC VARIABILITY IN CLONED CATTLE FETUSES FROM ONE CELL LINE THAN CONTEMPORARY HALF-SIBS GENERATED BY ARTIFICIAL INSEMINATION OR IN VITRO EMBRYO PRODUCTION

2004 ◽  
Vol 16 (2) ◽  
pp. 148
Author(s):  
R.S.F. Lee ◽  
J. Peterson ◽  
D.N. Wells
Keyword(s):  
Cell Line ◽  
Artificial Insemination ◽  
Phenotypic Variability ◽  
Cell Types ◽  
Fetal Membrane ◽  
Placental Development ◽  
Culture Methods ◽  
Donor Genome ◽  
Genetic Traits

The cloning of cattle by somatic cell nuclear transfer (NT) is associated with considerable variation in developmental abnormalities. Some of this variation may be due to the cell types/lines used and the specific production and culture methods for NT embryos. Fetal and placental development were studied in 24 pregnancies generated by NT (Wells et al., 2003 Theriogenology 59, 45–59) from a granulosa cell line. The controls consisted of 11 and 14 pregnancies resulting from in vitro-produced embryos (IVP) and artificial insemination (AI), respectively. All fetuses shared the same Friesian sire; oocytes for the derivation of NT or IVP embryos were obtained from abattoir-derived ovaries of Friesian cows. Morphometric measurements were made on the fetuses, fetal membranes, fluid volumes and placentomes at Days 50, 100 and 150 of gestation after slaughter. Pairwise comparisons of within group variances between the treatment groups were made using the F-test. The pregnancy loss from AI or embryo transfer to Day 150 was ∼40% for the AI and IVP groups. However, 60% of NT embryos transferred had been lost by Day 150. NT fetal weights at Day 100 were more variable than for the AI (P<0.001) and IVP (P<0.05) groups. The NT crown-rump lengths were also more variable compared with the IVP (P<0.05) but not the AI group. At Day 100, NT heart (P<0.01), kidney (P<0.01) and liver (P<0.05) weights were more variable compared with the AI group; both liver (P<0.05) and kidney (P<0.01) weights were similarly more variable in the Day 150 NT group. Part of this variability may be due to disproportionate organ growth in NT fetuses. Increased variability was most evident in the utero-placental tissues. At Day 50, the total fetal membrane weights were more variable in the NT compared with the AI (P<0.001) but not the IVP group. The Day 50 IVP membrane weights were also more variable (P<0.05) than for the AI group. The greater variability of the Day 150 NT membrane weights, when compared with AI (P<0.05) or IVP (P<0.01), could be due partly to greater variation in the allantoic and amniotic fluid volumes. Placentome numbers were significantly lower in the surviving Day 100 NT pregnancies but the weights of the total maternal caruncular tissue of the placentomes were significantly higher and more variable in the NT group (P<0.05 for both AI and IVP). Placentome numbers in surviving NT pregnancies at Day 150 were similar to the controls. However, the total caruncle weights in both the NT and IVP groups were more variable when compared with the AI group (P<0.05 for both). Thus, there is greater variability in fetal membrane and placental development in NT and, to a certain extent, IVP fetuses, when compared with the AI group. The increased variability within this NT group suggests that epigenetic effects arising from incomplete reprogramming of the donor genome and embryo culture can override genetic traits to a certain extent. Supported by FRST C10X0018.

scholarly journals Integrating High-Throughput Approaches and in vitro Human Trophoblast Models to Decipher Mechanisms Underlying Early Human Placenta Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Bum-Kyu Lee ◽  
Jonghwan Kim
Keyword(s):  
High Throughput ◽  
Human Placenta ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
Cell Types ◽  
Model Systems ◽  
Extravillous Trophoblast ◽  
Human Trophoblast ◽  
Early Human

The placenta is a temporary but pivotal organ for human pregnancy. It consists of multiple specialized trophoblast cell types originating from the trophectoderm of the blastocyst stage of the embryo. While impaired trophoblast differentiation results in pregnancy disorders affecting both mother and fetus, the molecular mechanisms underlying early human placenta development have been poorly understood, partially due to the limited access to developing human placentas and the lack of suitable human in vitro trophoblast models. Recent success in establishing human trophoblast stem cells and other human in vitro trophoblast models with their differentiation protocols into more specialized cell types, such as syncytiotrophoblast and extravillous trophoblast, has provided a tremendous opportunity to understand early human placenta development. Unfortunately, while high-throughput research methods and omics tools have addressed numerous molecular-level questions in various research fields, these tools have not been widely applied to the above-mentioned human trophoblast models. This review aims to provide an overview of various omics approaches that can be utilized in the study of human in vitro placenta models by exemplifying some important lessons obtained from omics studies of mouse model systems and introducing recently available human in vitro trophoblast model systems. We also highlight some key unknown questions that might be addressed by such techniques. Integrating high-throughput omics approaches and human in vitro model systems will facilitate our understanding of molecular-level regulatory mechanisms underlying early human placenta development as well as placenta-associated complications.

scholarly journals Per- and Polyfluoroalkyl Substances Differentially Inhibit Placental Trophoblast Migration and Invasion In Vitro

2020 ◽  
Vol 175 (2) ◽  
pp. 210-219 ◽  
Author(s):  
John T Szilagyi ◽  
Anastasia N Freedman ◽  
Stewart L Kepper ◽  
Arjun M Keshava ◽  
Jackie T Bangma ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Cell Types ◽  
The United States ◽  
Trophoblast Invasion ◽  
Migration And Invasion ◽  
Placental Blood ◽  
Polyfluoroalkyl Substances ◽  
The Stability ◽  
Trophoblast Migration

Abstract Per- and polyfluoroalkyl substances (PFAS) are used as industrial surfactants and chemical coatings for household goods such as Teflon. Despite regulatory efforts to phase out legacy PFAS, they remain detectable in drinking water throughout the United States. This is due to the stability of legacy PFAS and the continued use of replacement compounds. In humans, PFAS have been detected in placenta and cord blood and are associated with low birth weight and preeclampsia risk. Preeclampsia is a leading cause of maternal mortality and is driven by insufficient endometrial trophoblast invasion, resulting in poor placental blood flow. PFAS alter invasion of other cell types, but their impact on trophoblasts is not understood. We therefore assessed the effects of PFAS on trophoblast migration, invasion, and gene expression in vitro. Trophoblast migration and invasion were assessed using a modified scratch assay in the absence or presence of Matrigel, respectively. Treatment with perfluorooctanoic sulfate (PFOS), perfluorooctanoic acid (PFOA), and GenX (1000 ng/ml) each decreased trophoblast migration over 24 h. However, only GenX (1000 ng/ml) significantly inhibited trophoblast invasion. Treatment with PFOS, PFOA, and GenX also decreased trophoblast expression of chemokines (eg, CCL2), chemokine receptors (eg, CCR4), and inflammatory enzymes (eg, ALOX15) involved in migration. Inhibition of chemokine receptors with pertussis toxin (10 ng/ml), a G-protein inhibitor, inhibited trophoblast migration similar to the PFAS. Taken together, PFAS decrease trophoblast migration, invasion, and inflammatory signaling. By understanding the mechanisms involved, it may be possible to identify the biological and exposure factors that contribute to preeclampsia.

Molecular mechanisms of platelet exocytosis: role of SNAP-23 and syntaxin 2 in dense core granule release

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 921-929 ◽  
Author(s):  
Dong Chen ◽  
Audrey M. Bernstein ◽  
Paula P. Lemons ◽  
Sidney W. Whiteheart
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Dominant Negative ◽  
Dense Core ◽  
Protein Receptors ◽  
Dense Core Granules ◽  
Platelet Exocytosis ◽  
Granule Release

To characterize the molecular mechanisms of platelet secretion, we focused on the calcium-induced exocytosis of dense core granules. Platelets contain several known t-SNAREs (soluble N-ethylmaleimide sensitive factor [NSF] attachment protein receptors) such as syntaxins 2, 4, and 7 and SNAP-23 (synaptosomal associated protein 23). By using an in vitro exocytosis assay, we have been able to assign roles for some of these t-SNAREs in dense core granule release. This calcium-induced secretion relies on the SNARE proteins because it is stimulated by the addition of recombinant -SNAP and inhibited by a dominant negative -SNAP–L294A mutant or by anti–-SNAP and anti-NSF antibodies. SNAP-23 antibodies and an inhibitory C-terminal SNAP-23 peptide both blocked dense core granule release, demonstrating a role for SNAP-23. Unlike other cell types, platelets contain a significant pool of soluble SNAP-23, which does not partition into Triton X-114. Of the anti-syntaxin antibodies tested, only anti–syntaxin 2 antibody inhibited dense core granule release. Immunoprecipitation studies showed that the 2 t-SNAREs syntaxin 2 and SNAP-23 do form a complex in vivo. These data clearly show that SNAPs, NSF, and specific t-SNAREs are used for dense core granule release; these data provide a greater understanding of regulated exocytosis in platelets.

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