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Børge Teisner - One of the best experts on this subject based on the ideXlab platform.
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transit amplifying ductular oval cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta like protein preadipocyte factor 1 Fetal Antigen 1
American Journal of Pathology, 2004Co-Authors: Charlotte Harken Jensen, Børge Teisner, Uffe Holmskov, Eva Irene Jauho, Eric Santonirugiu, Niels Tygstrup, Hanne Cathrine BisgaardAbstract:Hepatic regeneration from toxic or surgical injury to the adult mammalian liver, endorses different cellular responses within the hepatic lineage. The molecular mechanisms determining commitment of a cell population at a specific lineage level to participate in liver repair as well as the fate of its progeny in the hostile environment created by the injury are not well defined. Based on the role of the Notch/Delta/Jagged system in cell fate specification and recent reports linking Notch signaling with normal bile duct formation in mouse and human liver, we examined the expression of Notch1, Notch2, Notch3, Delta1, Delta3, Jagged1, and Jagged2, and delta-like protein/preadipocyte factor 1/Fetal Antigen 1 (dlk) in four well-defined experimental rat models of liver injury and regeneration. Although Delta3 and Jagged2 were undetectable by reverse transcriptase-polymerase chain reaction and Northern blot, we observed the most significant up-regulation of all other transcripts in the 2-acetylaminofluorene-70% hepatectomy (AAF/PHx) model, in which liver mass is restored by proliferation and differentiation of transit-amplifying ductular (oval) cells. The most profound change was observed for dlk. Accordingly, immunohistochemical analyses in the AAF/PHx model showed a specific expression of dlk in atypical ductular structures composed of oval cells. Delta-like protein was not observed in proliferating hepatocytes or bile duct cells after partial hepatectomy or ligation of the common bile duct whereas clusters of dlk immunoreactive oval cells were found in both the retrorsine and the AAF/PHx models. Finally, we used dlk to isolate α-fetoprotein-positive cells from Fetal and adult regenerating rat liver by a novel antibody panning technique.
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expression biosynthesis and release of preadipocyte factor 1 delta like protein Fetal Antigen 1 in pancreatic beta cells possible physiological implications
Journal of Endocrinology, 2003Co-Authors: Birgitte Nissen Friedrichsen, Charlotte Harken Jensen, Børge Teisner, Carina Carlsson, Annette Moldrup, B Michelsen, Jens NielsenAbstract:Preadipocyte factor-1 (Pref-1)/delta-like protein/Fetal Antigen-1 (FA1) is a member of the epidermal growth factor-like family. It is widely expressed in embryonic tissues, whereas in adults it is confined to the adrenal gland, the anterior pituitary, the endocrine pancreas, the testis and the ovaries. We have previously cloned Pref-1 from neonatal rat islets stimulated by GH. The aim of the present study was to elucidate the biosynthesis and release of Pref-1/FA1 in -cells and to determine if Pref-1/FA1 is mediating the mitogenic effect of GH in insulinproducing cells. First we studied the biosynthesis and processing of Pref-1 to the soluble form, FA1, in pancreatic islets and insulinoma cells transfected with Pref-1 cDNA. We measured the release of FA1 by ELISA and the possible effect of FA1 in GH-stimulated -cell proliferation by incorporation of bromodeoxyuridine (BrdU) in insulin-positive islet cells. We found that Pref-1 was synthesized in normal islets and in RINm5F insulinoma cells and released into the medium in two forms, of which one corresponded to FA1. Both the expression of the mRNA for Pref-1 and the release of the soluble form(s) were stimulated by GH and prolactin (PRL). Whereas 2 h exposure to high glucose or 3-isobutyl-1-methylxanthine stimulated insulin release, only a small change was seen in FA1 release, suggesting that the FA1 is released by a different pathway than insulin. However, long-term exposure (48 h) to high glucose increased FA1 secretion, indicating that FA1 is regulated by glucose. Neither FA1 nor conditioned medium from GH-stimulated islets depleted for GH was able to increase -cell replication and overexpression of Pref-1 resulted in attenuated proliferation of the RINm5F cells. By immunocytochemistry of GH-stimulated islet cells no correlation between high Pref-1 expression and BrdU incorporation was observed and there was an inverse relationship between the levels of insulin and Pref-1. These results indicate that Pref-1/FA1 is not mediating the mitogenic effect of GH and PRL. Therefore the function of Pref-1 in the -cell remains unknown.
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Fetal Antigen 1 in Healthy Adults and Patients with Pituitary Disease: Relation to Physiological, Pathological, and Pharmacological GH Levels
The Journal of clinical endocrinology and metabolism, 2001Co-Authors: Marianne Andersen, Charlotte Harken Jensen, Børge Teisner, Henrik Daa Schrøder, René Klinkby Støving, J.b. Larsen, Claus HagenAbstract:Immunohistochemical analysis of the distribution of human Fetal Antigen 1 (FA1) in adult human tissues has demonstrated a strong association between FA1 and (neuro)endocrine structures. In the anterior pituitary gland FA1 was colocalized with GH, and the present study was performed to evaluate a possible relationship between GH and FA1. FA1 and GH levels were measured during a 24-h period at 20-min intervals. In contrast to the known GH peaks during 24-h sampling, there was no detectable FA1 peak. The FA1 responses to placebo were not significantly different from the responses to the combination of pyridostigmine and GHRH. No significant difference was found between basal FA1 (nanograms per ml) levels [median (minimum–maximum)] in healthy adults [n = 40; 28.6 ng/ml (12.5–72.0)], acromegalic patients [n = 11; 31.0 ng/ml (21.6–56.3)], and patients with GH deficiency [n = 22; 32.1 ng/ml (13.4–108.7)]. FA1 levels were significantly reduced, in the six of seven acromegalic GH responders to octreotide, from [me...
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Fetal Antigen 1, an EGF multidomain protein in the sex hormone-producing cells of the gonads and the microenvironment of germ cells
Molecular human reproduction, 1999Co-Authors: Charlotte Harken Jensen, Karin Erb, L.g. Westergaard, Anette Kliem, Børge TeisnerAbstract:Fetal Antigen 1 (FA1), an epidermal growth factor (EGF) multidomain glycoprotein, was investigated in the human reproductive system. Immunohistochemical analysis of the male reproductive system revealed staining for FA1 in the Leydig cells only. Concentrations of FA1 in seminal plasma and serum were similar and significantly correlated in weekly samples from three men (P 20 x 10(6)/ml, compared with those with counts
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Elevated Serum Levels of Fetal Antigen 1,a Member of the Epidermal Growth Factor Superfamily, in Patients with Small Cell Lung Cancer
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 1999Co-Authors: Charlotte Harken Jensen, Lars Drivsholm, Inga Laursen, Børge TeisnerAbstract:Serum levels of Fetal Antigen 1 (FA1) were quantified pretherapeutically in 16 patients with pneumonia, 30 patients with small cell lung cancer (SCLC) and 10 patients with non-small cell lung cancer (
Charlotte Harken Jensen - One of the best experts on this subject based on the ideXlab platform.
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characterization of Fetal Antigen 1 delta like 1 homologue expressing cells in the rat nigrostriatal system effects of a unilateral 6 hydroxydopamine lesion
PLOS ONE, 2015Co-Authors: Remy Liechti, Charlotte Harken Jensen, Angelique Ducray, Pia Jensen, Stefano Di Santo, Stefanie Seiler, Morten Meyer, Hans Rudolf WidmerAbstract:Fetal Antigen 1/delta-like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been suggested as a potential supplementary marker of dopaminergic neurons. The present study aimed at investigating the distribution of FA1/dlk1-immunoreactive (-ir) cells in the early postnatal and adult midbrain as well as in the nigrostriatal system of 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA-mediated loss of FA1/dlk1-expressing SNc dopaminergic neurons and/or due to the stab wound. Our findings hint to a significant role of FA1/dlk1 in the SNc during early postnatal development. The differential expression of FA1/dlk1 in the SNc and the striatum of dopamine-depleted rats could indicate a potential involvement of FA1/dlk1 in the cellular response to the degenerative processes.
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delta like 1 Fetal Antigen 1 dlk1 fa1 is a novel regulator of chondrogenic cell differentiation via inhibition of the akt kinase dependent pathway
Journal of Biological Chemistry, 2011Co-Authors: Li Zi-chen, Basem M. Abdallah, Charlotte Harken Jensen, Diyako Werya Mohamed Qanie, Abbas Jafari, Maria Luisa Nueda Sanz, Annamarja Saamanen, Hanna Taipaleenmäki, Jorge Laborda, Moustapha KassemAbstract:Delta-like 1 (Dlk1, also known as Fetal Antigen-1, FA1) is a member of Notch/Delta family that inhibits adipocyte and osteoblast differentiation; however, its role in chondrogenesis is still not clear. Thus, we overexpressed Dlk1/FA1 in mouse embryonic ATDC5 cells and tested its effects on chondrogenic differentiation. Dlk1/FA1 inhibited insulin-induced chondrogenic differentiation as evidenced by reduction of cartilage nodule formation and gene expression of aggrecan, collagen Type II and X. Similar effects were obtained either by using Dlk1/FA1-conditioned medium or by addition of a purified, secreted, form of Dlk1 (FA1) directly to the induction medium. The inhibitory effects of Dlk1/FA1 were dose-dependent and occurred irrespective of the chondrogenic differentiation stage: proliferation, differentiation, maturation, or hypertrophic conversion. Overexpression or addition of the Dlk1/FA1 protein to the medium strongly inhibited the activation of Akt, but not the ERK1/2, or p38 MAPK pathways, and the inhibition of Akt by Dlk1/FA1 was mediated through PI3K activation. Interestingly, inhibition of fibronectin expression by siRNA rescued the Dlk1/FA1-mediated inhibition of Akt, suggesting interaction of Dlk1/FA1 and fibronectin in chondrogenic cells. Our results identify Dlk1/FA1 as a novel regulator of chondrogenesis and suggest Dlk1/FA1 acts as an inhibitor of the PI3K/Akt pathways that leads to its inhibitory effects on chondrogenesis.
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Delta-like 1/Fetal Antigen-1 (Dlk1/FA1) Is a Novel Regulator of Chondrogenic Cell Differentiation via Inhibition of the Akt Kinase-dependent Pathway
The Journal of biological chemistry, 2011Co-Authors: Li Zi-chen, Basem M. Abdallah, Charlotte Harken Jensen, Diyako Werya Mohamed Qanie, Abbas Jafari, Maria Luisa Nueda Sanz, Annamarja Saamanen, Hanna Taipaleenmäki, Jorge Laborda, Moustapha KassemAbstract:Delta-like 1 (Dlk1, also known as Fetal Antigen-1, FA1) is a member of Notch/Delta family that inhibits adipocyte and osteoblast differentiation; however, its role in chondrogenesis is still not clear. Thus, we overexpressed Dlk1/FA1 in mouse embryonic ATDC5 cells and tested its effects on chondrogenic differentiation. Dlk1/FA1 inhibited insulin-induced chondrogenic differentiation as evidenced by reduction of cartilage nodule formation and gene expression of aggrecan, collagen Type II and X. Similar effects were obtained either by using Dlk1/FA1-conditioned medium or by addition of a purified, secreted, form of Dlk1 (FA1) directly to the induction medium. The inhibitory effects of Dlk1/FA1 were dose-dependent and occurred irrespective of the chondrogenic differentiation stage: proliferation, differentiation, maturation, or hypertrophic conversion. Overexpression or addition of the Dlk1/FA1 protein to the medium strongly inhibited the activation of Akt, but not the ERK1/2, or p38 MAPK pathways, and the inhibition of Akt by Dlk1/FA1 was mediated through PI3K activation. Interestingly, inhibition of fibronectin expression by siRNA rescued the Dlk1/FA1-mediated inhibition of Akt, suggesting interaction of Dlk1/FA1 and fibronectin in chondrogenic cells. Our results identify Dlk1/FA1 as a novel regulator of chondrogenesis and suggest Dlk1/FA1 acts as an inhibitor of the PI3K/Akt pathways that leads to its inhibitory effects on chondrogenesis.
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human serum levels of Fetal Antigen 1 fa1 dlk1 increase with obesity are negatively associated with insulin sensitivity and modulate inflammation in vitro
International Journal of Obesity, 2008Co-Authors: Matilde R Chacon, Charlotte Harken Jensen, Merce Miranda, Jose Manuel Fernandezreal, Nuria Vilarrasa, Cristina Gutierrez, Jose Manuel Gomez, Joan VendrellAbstract:Human serum levels of Fetal Antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro
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Human serum levels of Fetal Antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro.
International journal of obesity (2005), 2008Co-Authors: Matilde R Chacon, Charlotte Harken Jensen, Merce Miranda, Nuria Vilarrasa, Cristina Gutierrez, Jose Manuel Gomez, José Manuel Fernández-real, Silvia Näf, Joan VendrellAbstract:Human serum levels of Fetal Antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro
Margaret G Petroff - One of the best experts on this subject based on the ideXlab platform.
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maternal cd4 and cd8 t cell tolerance towards a Fetal minor histocompatibility Antigen in t cell receptor transgenic mice
Biology of Reproduction, 2013Co-Authors: Antoine Perchellet, Susmita Jasti, Margaret G PetroffAbstract:ABSTRACT Tolerance of the maternal immune system in pregnancy is important for successful pregnancy because the semiallogeneic fetus may be subject to antiFetal responses. We examined maternal tolerance to the fetus using a murine system in which a model paternally inherited Antigen, ovalbumin (OVA), is expressed exclusively in the fetus and placenta. By employing T cell receptor (TCR) transgenic mice specific for major histocompatibility complex class I- or class II-restricted epitopes of OVA (OT-I and OT-II) as mothers, we investigated the fate of fetus-specific CD8+ and CD4+ T cells, respectively, during gestation. Both OVA-specific CD8+ and CD4+ T cells displayed an activated phenotype in the peripheral lymphoid tissues of OVA-bred OT-I and OT-II mice, consistent with their encounter of Fetal Antigen. Whereas a small percentage of OVA-specific CD4+ T cells were deleted in the periphery and thymus of OVA-bred OT-II mice, with evidence of TCR downregulation in the remaining T cells, deletion and TCR dow...
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Review: Fetal Antigens--identity, origins, and influences on the maternal immune system.
Placenta, 2011Co-Authors: Margaret G PetroffAbstract:Pregnancy induces priming of the maternal cellular and humoral immune systems. The paternally-inherited Fetal Antigens that influence maternal T and B cells include both major and minor histocompatibility Antigens - the same Antigens that are problematic in allotransplantation. Animal models have facilitated our understanding of the lymphocyte responses to Fetal Antigens, and our appreciation of the parallel response in pregnant women is increasing. The physiologic properties of the placenta as well as trafficking of cells between mother and fetus allow ample opportunity for sampling of Fetal proteins by the maternal immune system. Here, the current state of knowledge of Fetal Antigen-specific lymphocyte responses in pregnancy is reviewed.
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Maternal PD-1 regulates accumulation of Fetal Antigen-specific CD8+ T cells in pregnancy.
Journal of reproductive immunology, 2009Co-Authors: Elizabeth S Taglauer, Thomas M Yankee, Margaret G PetroffAbstract:The failure to reject the semi-allogeneic fetus suggests that maternal T lymphocytes are regulated by potent mechanisms in pregnancy. The T cell immunoinhibitory receptor, Programmed Death-1 (PD-1), and its ligand, B7-H1, maintain peripheral tolerance by inhibiting activation of self-reactive lymphocytes. Here, we investigated the role of the PD-1/B7-H1 pathway in maternal tolerance of the fetus. Antigen-specific maternal T cells both proliferate and upregulate PD-1 in vivo at mid-gestation in response to paternally inherited Fetal Antigen. In addition, when these cells carry a null deletion of PD-1, they accumulate excessively in the uterus-draining lymph nodes (P
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Maternal PD-1 regulates accumulation of Fetal Antigen-specific CD8+ T cells in pregnancy
Journal of Reproductive Immunology, 2009Co-Authors: Elizabeth S Taglauer, Thomas M Yankee, Margaret G PetroffAbstract:Abstract The failure to reject the semi-allogeneic fetus suggests that maternal T lymphocytes are regulated by potent mechanisms in pregnancy. The T cell immunoinhibitory receptor, Programmed Death-1 (PD-1), and its ligand, B7-H1, maintain peripheral tolerance by inhibiting activation of self-reactive lymphocytes. Here, we investigated the role of the PD-1/B7-H1 pathway in maternal tolerance of the fetus. Antigen-specific maternal T cells both proliferate and upregulate PD-1 in vivo at mid-gestation in response to paternally inherited Fetal Antigen. In addition, when these cells carry a null deletion of PD-1, they accumulate excessively in the uterus-draining lymph nodes ( P In vitro assays showed that apoptosis of Antigen-specific CD8 + PD-1 −/− cells was reduced following peptide stimulation, suggesting that the accumulation of these cells in maternal lymph nodes is due to decreased cell death. However, the absence of neither maternal PD-1 nor B7-H1 had detectable effects on gestation length, litter size, or pup weight at birth in either syngeneic or allogeneic pregnancies. These results suggest that PD-1 plays a previously unrecognized role in maternal–Fetal tolerance by inducing apoptosis of paternal Antigen-specific T cells during pregnancy, thereby controlling their abundance.
Moustapha Kassem - One of the best experts on this subject based on the ideXlab platform.
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Serum levels of Fetal Antigen 1 in extreme nutritional States.
ISRN endocrinology, 2012Co-Authors: Alin Andries, Basem M. Abdallah, Andreas Niemeier, René Klinkby Støving, Anna-maria Wolf, Kirsten Hørder, Moustapha KassemAbstract:Objective. Recent data suggest that Fetal Antigen (FA1) is linked to disorders of body weight. Thus, we measured FA1 serum levels in two extreme nutritional states of morbid obesity (MO) and anorexia nervosa (AN) and monitored its response to weight changes. Design. FA1 and insulin serum concentrations were assessed in a cross-sectional study design at defined time points after gastric restrictive surgery for 25 MO patients and 15 women with AN. Results. Absolute FA1 serum levels were within the assay normal range and were not different between the groups at baseline. However, the ratio of FA1/BMI was significantly higher in AN. FA1 was inversely correlated with BMI before and after weight change in AN, but not in MO patients. In addition, MO patients displayed a significant concomitant decrease of FA1 and insulin with the first 25% of EWL, while in AN patients a significant increase of FA1 was observed in association with weight gain. Conclusion. FA1 is a sensitive indicator of metabolic adaptation during weight change. While FA1 serum levels in humans generally do not correlate with BMI, our results suggest that changes in FA1 serum levels reflect changes in adipose tissue turnover.
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delta like 1 Fetal Antigen 1 dlk1 fa1 is a novel regulator of chondrogenic cell differentiation via inhibition of the akt kinase dependent pathway
Journal of Biological Chemistry, 2011Co-Authors: Li Zi-chen, Basem M. Abdallah, Charlotte Harken Jensen, Diyako Werya Mohamed Qanie, Abbas Jafari, Maria Luisa Nueda Sanz, Annamarja Saamanen, Hanna Taipaleenmäki, Jorge Laborda, Moustapha KassemAbstract:Delta-like 1 (Dlk1, also known as Fetal Antigen-1, FA1) is a member of Notch/Delta family that inhibits adipocyte and osteoblast differentiation; however, its role in chondrogenesis is still not clear. Thus, we overexpressed Dlk1/FA1 in mouse embryonic ATDC5 cells and tested its effects on chondrogenic differentiation. Dlk1/FA1 inhibited insulin-induced chondrogenic differentiation as evidenced by reduction of cartilage nodule formation and gene expression of aggrecan, collagen Type II and X. Similar effects were obtained either by using Dlk1/FA1-conditioned medium or by addition of a purified, secreted, form of Dlk1 (FA1) directly to the induction medium. The inhibitory effects of Dlk1/FA1 were dose-dependent and occurred irrespective of the chondrogenic differentiation stage: proliferation, differentiation, maturation, or hypertrophic conversion. Overexpression or addition of the Dlk1/FA1 protein to the medium strongly inhibited the activation of Akt, but not the ERK1/2, or p38 MAPK pathways, and the inhibition of Akt by Dlk1/FA1 was mediated through PI3K activation. Interestingly, inhibition of fibronectin expression by siRNA rescued the Dlk1/FA1-mediated inhibition of Akt, suggesting interaction of Dlk1/FA1 and fibronectin in chondrogenic cells. Our results identify Dlk1/FA1 as a novel regulator of chondrogenesis and suggest Dlk1/FA1 acts as an inhibitor of the PI3K/Akt pathways that leads to its inhibitory effects on chondrogenesis.
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dlk1 is a novel regulator of bone mass that mediates estrogen deficiency induced bone loss in mice
Journal of Bone and Mineral Research, 2011Co-Authors: Nicholas Ditzel, Basem M. Abdallah, Maria Jose Ruizhidalgo, Gunnhildur Asta Traustadottir, Amer Mahmood, Arndt F. Schilling, Jorge Laborda, Michael Amling, Moustapha KassemAbstract:Delta-like 1/Fetal Antigen 1 (DLK1/FA-1) is a transmembrane protein belonging to the Notch/Delta family that acts as a membrane-associated or a soluble protein to regulate regeneration of a number of adult tissues. Here we examined the role of DLK1/FA-1 in bone biology using osteoblast-specific Dlk1-overexpressing mice (Col1-Dlk1). Col1-Dlk1 mice displayed growth retardation and significantly reduced total body weight and bone mineral density (BMD). Micro–computed tomographis (µCT) scanning revealed a reduced trabecular and cortical bone volume fraction. Tissue-level histomorphometric analysis demonstrated decreased bone-formation rate and enhanced bone resorption in Col1-Dlk1 mice compared with wild-type mice. At a cellular level, Dlk1 markedly reduced the total number of bone marrow (BM)–derived colony-forming units fibroblasts (CFU-Fs), as well as their osteogenic capacity. In a number of in vitro culture systems, Dlk1 stimulated osteoclastogenesis indirectly through osteoblast-dependent increased production of proinflammatory bone-resorbing cytokines (eg, Il7, Tnfa, and Ccl3). We found that ovariectomy (ovx)–induced bone loss was associated with increased production of Dlk1 in the bone marrow by activated T cells. Interestingly, Dlk1−/− mice were significantly protected from ovx-induced bone loss compared with wild-type mice. Thus we identified Dlk1 as a novel regulator of bone mass that functions to inhibit bone formation and to stimulate bone resorption. Increasing DLK1 production by T cells under estrogen deficiency suggests its possible use as a therapeutic target for preventing postmenopausal bone loss. © 2011 American Society for Bone and Mineral Research.
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Delta-like 1/Fetal Antigen-1 (Dlk1/FA1) Is a Novel Regulator of Chondrogenic Cell Differentiation via Inhibition of the Akt Kinase-dependent Pathway
The Journal of biological chemistry, 2011Co-Authors: Li Zi-chen, Basem M. Abdallah, Charlotte Harken Jensen, Diyako Werya Mohamed Qanie, Abbas Jafari, Maria Luisa Nueda Sanz, Annamarja Saamanen, Hanna Taipaleenmäki, Jorge Laborda, Moustapha KassemAbstract:Delta-like 1 (Dlk1, also known as Fetal Antigen-1, FA1) is a member of Notch/Delta family that inhibits adipocyte and osteoblast differentiation; however, its role in chondrogenesis is still not clear. Thus, we overexpressed Dlk1/FA1 in mouse embryonic ATDC5 cells and tested its effects on chondrogenic differentiation. Dlk1/FA1 inhibited insulin-induced chondrogenic differentiation as evidenced by reduction of cartilage nodule formation and gene expression of aggrecan, collagen Type II and X. Similar effects were obtained either by using Dlk1/FA1-conditioned medium or by addition of a purified, secreted, form of Dlk1 (FA1) directly to the induction medium. The inhibitory effects of Dlk1/FA1 were dose-dependent and occurred irrespective of the chondrogenic differentiation stage: proliferation, differentiation, maturation, or hypertrophic conversion. Overexpression or addition of the Dlk1/FA1 protein to the medium strongly inhibited the activation of Akt, but not the ERK1/2, or p38 MAPK pathways, and the inhibition of Akt by Dlk1/FA1 was mediated through PI3K activation. Interestingly, inhibition of fibronectin expression by siRNA rescued the Dlk1/FA1-mediated inhibition of Akt, suggesting interaction of Dlk1/FA1 and fibronectin in chondrogenic cells. Our results identify Dlk1/FA1 as a novel regulator of chondrogenesis and suggest Dlk1/FA1 acts as an inhibitor of the PI3K/Akt pathways that leads to its inhibitory effects on chondrogenesis.
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dlk1 fa1 is a novel endocrine regulator of bone and fat mass and its serum level is modulated by growth hormone
Endocrinology, 2007Co-Authors: Basem M. Abdallah, Nicholas Ditzel, Charlotte Harken Jensen, Ming Ding, Allan Flyvbjerg, Thomas G Jensen, Frederik Dagnaeshansen, Jurg A Gasser, Moustapha KassemAbstract:Fat and bone metabolism are two linked processes regulated by several hormonal factors. Fetal Antigen 1 (FA1) is the soluble form of dlk1 (delta-like 1), which is a member of the Notch-Delta family. We previously identified FA1 as a negative regulator of bone marrow mesenchymal stem cell differentiation. Here, we studied the effects of circulating FA1 on fat and bone mass in vivo by generating mice expressing high serum levels of FA1 (FA1 mice) using the hydrodynamic-based gene transfer procedure. We found that increased serum FA1 levels led to a significant reduction in total body weight, fat mass, and bone mass in a dose-dependent manner. Reduced bone mass in FA1 mice was associated with the inhibition of mineral apposition rate and bone formation rates by 58 and 72%, respectively. Because FA1 is colocalized with GH in the pituitary gland, we explored the possible modulation of serum FA1 by GH. Serum levels of IGF-I and IGF binding proteins did not change in FA1 mice, whereas increasing serum GH in norm...
B Teisner - One of the best experts on this subject based on the ideXlab platform.
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Fetal Antigen 1 an egf multidomain protein in the sex hormone producing cells of the gonads and the microenvironment of germ cells
Molecular Human Reproduction, 1999Co-Authors: Charlotte Harken Jensen, Karin Erb, L.g. Westergaard, Anette Kliem, B TeisnerAbstract:Fetal Antigen 1 (FA1), an epidermal growth factor (EGF) multidomain glycoprotein, was investigated in the human reproductive system. Immunohistochemical analysis of the male reproductive system revealed staining for FA1 in the Leydig cells only. Concentrations of FA1 in seminal plasma and serum were similar and significantly correlated in weekly samples from three men (P 20 x 10(6)/ml, compared with those with counts theca interna and the hilus cells but not in the granulosa cells or the oocyte. In follicular fluid the concentration of FA1 (median; 73.3 ng/ml, n = 28) was three times higher than that of serum (median; 23.8 ng/ml). These data suggest a role for this novel member of the EGF superfamily in relation to human reproduction, but further experiments are needed to define the biological function and to elucidate its clinical potential.
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Fetal Antigen 1 fa1 a circulating member of the epidermal growth factor egf superfamily elisa development physiology and metabolism in relation to renal function
Clinica Chimica Acta, 1997Co-Authors: Charlotte Harken Jensen, Thomas N. Krogh, René Klinkby Støving, Uffe Holmskov, B TeisnerAbstract:Abstract We describe an ELISA technique for quantification of Fetal Antigen 1 (FA1), a glycoprotein belonging to the EGF-superfamily. The ELISA is based on immunospecifically purified polyclonal antibodies and has a dynamic range of 0.7–5.3 ng/ml, intra- and inter-assay C.V.s of less than 3.2% and an average recovery of 105% in serum and 98% in urine. Comparison of FA1 in amniotic fluid, serum and urine revealed parallel titration curves, identical elution volumes following size chromatography, immunological identity and similar profiles when analysed by MALDI–MS. The reference interval for serum FA1 was 12.3–46.6 ng/ml and the levels were 10 times higher in patients with renal failure. FA1 showed no diurnal variation, no variation during the menstrual cycle and was not influenced by the acute phase reaction. In humans (n=10) the renal clearance of FA1 was 11 ml/min and an identical high renal clearance was found in rats when expressed per 100 g body weight. In rats the initial increase in serum FA1 was 10 ng/ml/h following bilateral nephrectomy, explaining the increased serum concentrations of FA1 observed in patients with renal failure.
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glycosylation analysis and protein structure determination of murine Fetal Antigen 1 mfa1 the circulating gene product of the delta like protein dlk preadipocyte factor 1 pref 1 and stromal cell derived protein 1 scp 1 cdnas
FEBS Journal, 1997Co-Authors: Thomas N. Krogh, Karsten Skjødt, B Teisner, Elin Bachmann, Peter HøjrupAbstract:By means of sequence analysis, murine Fetal Antigen 1 (mFAl) isolated from Mus musculus amniotic fluid was shown to be the circulating protein of the δ-like protein, stromal-cell-derived protein 1 (SCP-1) and preadipocyte factor 1 (Pref-1) gene products. The protein contains 36 cysteine residues arranged in six epidermal-growth-factor-like domains. The purification of several C-terminal peptides of varying lengths showed mFA1 to be C-terminal heterogeneous. O-linked glycosylations of the NeuNAcα2–3Galβ1- 3(NeuNAcα2–6)GalNAc type were present on all C-terminal peptides at residues Thr235, Thr244 and Thr248, although glycosylation on Thr244 was only partial. Three N-linked glycosylations were localized in mFA1 (Asn77, Asn142 and Asn151), two of which (Asn142 and Asn151) were in the unusual Asn-Xaa-Cys motif. Fucosylated biantennary complex-type and small amounts (less than 5%) of triantennary complex-type structures were identified on the glycosylated asparagine residues using sequential exoglycosidase and endoglycosidase digestions combined with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The presence of O-linked monosaccharides (glucose attached to Ser71, Serl93 and fucose at Thr201) was tentatively ascertained by combining Edman degradation and MALDI-MS. The results presented shows mFA1 to be the circulating heterogeneous cleavage products of the membrane-bound protein encoded by the murine cDNAs dlk, pref-1 and SCP-1.