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PubMed2001

Trophoblast giant-cell differentiation involves changes in cytoskeleton and cell motility.

Trophoblast giant-cell differentiation is well-characterized at the molecular level, yet very little is known about how molecular changes affect the cellular functions of trophoblast in embryo implantation. We have found, using both explanted E7.5 mouse embryo ectoplacental cone and the rat choriocarcinoma (Rcho-1) cell line, that trophoblast differentiation is distinguished by dramatic changes in cytoarchitecture and cell behavior. Undifferentiated trophoblast cells contain little organized actin and few small, peripheral focal complexes and exhibit high membrane protrusive activity, while differentiated trophoblast giant cells contain prominent stress fibers, large internal as well as peripheral focal adhesions, and become immotile. The dramatic changes in cell behavior and cytoskeletal organization of giant cells correlate with changes in the activities of the Rho family of small GTPases and a decrease in tyrosine phosphorylation of focal adhesion kinase. Together, these data provide detailed insight into the cellular properties of trophoblast giant cells and suggest that giant-cell differentiation is characterized by a transition from a motile to a specialized epithelial phenotype. Furthermore, our data support a phagocytic erosion, rather than a migratory infiltration, mechanism for trophoblast giant-cell invasion of the uterine stroma.

Actins↗
PubMed2006

Short exposure to Notch ligand Delta-4 is sufficient to induce T-cell differentiation program and to increase the T cell potential of primary human CD34+ cells.

OBJECTIVE: The Notch pathway plays a key role in cell fate choices and in T-cell development. The goal of our study was to evaluate whether a short in vitro stimulation of the Notch pathway may alter human progenitor cell behavior. METHODS: CD34+ cord blood progenitors were exposed for 4 days to either immobilized Notch ligand Delta-4 or in control conditions. Phenotypic and molecular changes induced by the short stimulation were assessed at day 4. Next, long-term alteration of the fate of these progenitors was assessed in culture conditions suitable for B (coculture with MS5 stromal cells) and T (FTOC and OP9 stromal cells expressing Delta-4 systems) cell differentiation. RESULTS: Notch activation was sufficient to trigger immunophenotypic and molecular changes consistent with early T-cell lineage differentiation. Delta-4 induced, in 4 days, CD7+cytCD3epsilon+ cells. This paralleled at the gene-transcription level with de novo expression of several T cell-related transcription factors and TCRgamma rearrangement, while B cell transcripts were simultaneous silenced. As compared to non-Delta-4 primed cells, these early changes translated to long-term alteration of the potential of cells. Delta-4 priming led to an acceleration of T-cell development, including a completion of the TCR rearrangement, when cells were cultured in systems suitable for T-cell development while B-cell development was inhibited. CONCLUSION: A transient Notch activation is sufficient to promote T-cell differentiation from cord blood CD34+ cells. This system may be a useful tool for the amplification and the quantification of the T potential of CD34+ cells in various disease conditions.

Adaptor Proteins, Signal Transducing↗
PubMed1997

p21WAF1/Cip1 expression is associated with cell differentiation but not with p53 mutations in squamous cell carcinomas of the larynx.

p21WAF1/Cip1 is a recently identified gene involved in cell cycle regulation through cyclin-CDK-complex inhibition. The expression of this gene in several cell lines seems to be induced by wild-type, but not mutant, p53. p21WAF1/Cip1 expression has been studied at both mRNA and protein levels in a series of 49 normal mucosae and squamous cell carcinomas of the larynx. A significant association was found between mRNA and protein expression in tumours (P < 0.0001). p21WAF1/Cip1 expression was strongly associated with squamous cell differentiation of carcinomas, because six of seven (86 per cent) undifferentiated carcinomas (grade 4) showed very low levels of p21WAF1/Cip1 expression, whereas 41 out of 42 (98 per cent) carcinomas with squamous cell differentiation (grades 1-3) had normal or high levels of p21WAF1/Cip1 expression (P < 0.0001). In addition, p21WAF1/Cip1 expression was topologically related to the squamous differentiation of tumour cells with a distribution similar to that seen in normal squamous epithelium. No correlation was found between p21WAF1/Cip1 expression and the global S-phase of the carcinomas. p53 mutations (exons 5-9) were found in ten carcinomas with p21WAF1/Cip1 expression, but no p53 mutations were detected in three p21WAF1/Cip1-negative tumours. In conclusion, p21WAF1/Cip1 expression is frequently upregulated in squamous cell carcinomas of the larynx and is associated with tumour cell differentiation. p21WAF1/Cip1 expression in these tumours is independent of p53 gene mutations.

Adult↗
PubMed2002

Gamma-tubulin in chicken erythrocytes: changes in localization during cell differentiation and characterization of cytoplasmic complexes.

The mechanism of marginal band (MB) formation in differentiating erythroid cells is not fully understood, and the proteins involved in nucleation of MB microtubules are largely unknown. To gain insights into the function of gamma-tubulin in MB formation, we have followed its distribution in developing chicken erythrocytes and characterized soluble forms of the protein. In early stages of erythroid cells differentiation, gamma-tubulin was present in microtubule-organizing centers, mitotic spindles, as well as on MB. Its subcellular localization changed in the course of differentiation, and in postnatal peripheral erythrocytes gamma-tubulin was found only in soluble forms. After cold-induced depolymerization gamma-tubulin in erythroid cells formed large clusters that were not observed in matured cells, and re-growth experiments demonstrated that gamma-tubulin was not present in distinct nucleation structures at the cell periphery. Soluble gamma-tubulin formed complexes of various size and large complexes were prone to dissociation in the presence of high salt concentration. Interaction of gamma-tubulin with tubulin dimers was revealed by precipitation experiments. gamma-Tubulin occurred in multiple charge variants whose number increased in the course of erythrocyte differentiation and corresponded with decreased binding to MB. The presented data demonstrate for the first time that gamma-tubulin is a substrate for developmentally regulated posttranslational modifications and that the binding properties of gamma-tubulin or its complexes change during differentiation events.

Animals↗
PubMed1990

PC12 cells differentiate into chromaffin cell-like phenotype in coculture with adrenal medullary endothelial cells.

Previously we described specific in vitro interactions between PC12 cells, a cloned, catecholamine-secreting pheochromocytoma cell line derived from the rat adrenal medulla, and bovine adrenal medullary endothelial cells. We now demonstrate that these interactions induce the PC12 cells to acquire physical and biochemical characteristics reminiscent of chromaffin cells. Under coculture conditions involving direct cell-cell contact, the endothelial cells and the PC12 cells reduced their rates of proliferation; upon prolonged coculture PC12 cells clustered into nests of cells similar to the organization of chromaffin cells seen in vivo. Within 3 days in coculture with endothelial cells, but not with unrelated control cells, PC12 cells synthesized increased levels of [Met]enkephalin. In addition, PC12 cells, growing on confluent endothelial monolayers, failed to extend neurites in response to nerve growth factor. Neither medium conditioned by endothelial cells nor fixed endothelial cells could by themselves induce all of these different phenomena in the PC12 cells. These results suggest that under coculture conditions PC12 cells change their state of differentiation toward a chromaffin cell-like phenotype. The rapid, transient increase in the expression of the protooncogene c-fos suggests that the mechanism(s) inducing the change in the state of differentiation in PC12 cells in coculture with the endothelial cells may be distinct from that described for the differentiation of PC12 cells--e.g., by glucocorticoids. We propose that similar interactions between endothelial cells and chromaffin cell precursors may occur during embryonic development and that these interactions might be instrumental for the organ-specific differentiation of the adrenal medulla in vivo.

Adrenal Gland Neoplasms↗
PubMed2003

Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation.

UNLABELLED: Signaling involved in osteoblastic cell differentiation remains largely unknown. This study further investigates mechanisms involved in BMP-2-induced osteoblastic cell differentiation. We report that BMP-2 can activate JNK and p38 in osteoblastic cells and provide evidences that these MAP kinases have distinct roles in regulating alkaline phosphatase and osteocalcin expression. INTRODUCTION: Bone morphogenetic protein (BMP)-2 exerts many of its biological effects through activation of the Smad pathway. Cooperative interactions between the Smads and the stress-activated protein kinase (SAPK) p38 and c-Jun-NH2-terminal kinase (JNK) pathways have recently been observed in TGF-beta signaling. MATERIALS AND METHODS: Activation of mitogen-activated protein (MAP) kinases by BMP-2 and the role of these signaling pathways for cell differentiation induced by BMP-2 was investigated in mouse MC3T3-E1 and primary cultured calvaria-derived osteoblastic cells using immunoprecipitation, in vitro kinase assay and Western blot analysis, as well as specific MAP kinase inhibitors. RESULTS: Associated with the rapid activation of Smads, BMP-2 barely affected extracellular-signal regulated kinase (ERK) activity, whereas it induced a transient activation of p38 and JNK. The role of p38 and JNK in mediating BMP-2-induced stimulation of osteoblastic cell differentiation was evaluated using the respective specific inhibitors SB203580 and SP600125. Inhibition of p38 by SB203580 was mainly associated with decreased alkaline phosphatase (ALP) activity, whereas inhibition of JNK by SP600125 was associated with a marked reduction in osteocalcin (OC) production induced by BMP-2. Corresponding alterations in ALP and OC mRNA levels were found in cells treated with BMP-2 and inhibitors, suggesting an implication of p38 and JNK pathways in BMP-2-induced osteoblastic cell differentiation at a transcriptional level. CONCLUSION: Data presented in this study describe p38 and JNK as new signaling pathways involved in BMP-2-induced osteoblastic cell differentiation with evidences for a distinct role of each MAP kinase in the control of alkaline phosphatase and osteocalcin expression.

3T3 Cells↗
PubMed1997

Insulin-like growth factor-I (IGF-I) and IGF binding protein-5 in Schwann cell differentiation.

Schwann cells (SCs) are the myelin producing cells of the peripheral nervous system. During development, SCs cease proliferation and differentiate into either a myelin-forming or non-myelin forming mature phenotype. We are interested in the role of insulin-like growth factor-I (IGF-I) in SC development. We have shown previously SCs proliferate in response to IGF-I in vitro. In the current study, we investigated the role of IGF-I in SC differentiation. SC differentiation was determined by morphological criteria and expression of myelin proteins. Addition of 1 mM 8-bromo cyclic AMP (cAMP) or growth on Matrigel matrix decreased proliferation and induced differentiation of SCs. IGF-I enhanced both cAMP and Matrigel matrix-induced SC differentiation, as assessed by both morphological criteria and myelin gene expression. Cultured SCs also express IGF binding protein-5 (IGFBP-5), which can modulate the actions of IGF-I. We examined the expression of IGFBP-5 during SC differentiation. Both cAMP and Matrigel matrix treatment enhanced IGFBP-5 protein expression and cAMP increased IGFBP-5 gene expression five fold. These findings suggest IGF-I potentiates SC differentiation. The concomitant up-regulation of IGFBP-5 may play a role in targeting IGF-I to SCs and thus increase local IGF-I bioavailability.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2005

Identification of inducible genes during mast cell differentiation.

Mast cells play an important role in allergic inflammation by releasing their bioactive mediators. The function of mast cells is enhanced by stimulation because of the induction of specific genes and their products. While many inducible genes have been elucidated, we speculated that a significant number of genes remain to be identified. Thus, we applied differential display (dd) PCR to establish a profile of the induced genes in bone marrow-derived mast cells (BMMCs) after they were co-cultured with 3T3 fibroblasts. To date, 150 cDNA fragments from the connective-type mast cells (CTMCs) were amplified. Among them, thirty cDNA fragments were reamplified for cloning and sequencing. The ddPCR strategy revealed that serine proteases were the most abundant genes among the sequenced clones induced during the maturation. Additionally, unknown genes from the co-culture of BMMCs with 3T3 fibroblasts were identified. We confirmed their induction in the CTMCs by Northern blot analysis and RT-PCR. Characterization of these induced genes during the maturation processes will provide insight into the functions of mast cells.

3T3 Cells↗
PubMed2000

Balance of two secretion pathways of nerve growth factor in PC12 cells changes during the progression of their differentiation, with a decrease in constitutive secretion in more differentiated cells.

Proteins are secreted from animal cells by either a constitutive or a regulated pathway. When cDNA of nerve growth factor (NGF) was introduced into PC12 cells, these cells produced and secreted active NGF, where NGF was secreted not only in constitutive but also in activity-dependent regulated way according to the results of pulse-chase and ELISA studies. The regulated secretion was caused by depolarization, cyclic AMP analogue, or beta-adrenergic agonist but not by glutamate or carbachol. Because these transfected cells differentiated into a morphology indistinguishable from that incubated with NGF protein, we next compared the secretion pathways of NGF from PC12 cells at different stages of the differentiation. NGF was secreted in both constitutive and regulated way at 2 and 7 days after the transfection of NGF-cDNA, but the constitutive secretion of NGF from the more differentiated cells of Day 7 was decreased and mature NGF tended to accumulate in the cells. These results indicate that the neurotrophin secretion mechanism is intimately regulated in the course of the differentiation of PC12 cells. Such a change in the protein secretion pathway might have an profound role in the development of neurons.

Animals↗
PubMed2004

Retroviral transduction of hematopoietic cells differentiated from human embryonic stem cell-derived CD45(neg)PFV hemogenic precursors.

Human embryonic stem cells (hESCs) provide a unique opportunity to study molecular mechanisms that regulate specification of the hematopoietic lineage in the human. Exploitation of this model using transgenic strategies depends on the ability to target cells of the hematopoietic lineage effectively and establish stable transgene expression. Here, a recently defined subpopulation of endothelial-like precursors derived from hESCs that is exclusively responsible for hematopoietic cell fate (CD45(neg)PFV) is shown to express GALVR-1 receptor and be efficiently transduced with GALV-pseudotyped retrovirus. Retroviral transduction, measured by enhanced green fluorescent protein, of hESC-derived CD45(+) cells differentiated from isolated CD45(neg)PFV precursors was 26.5 +/- 13% with 5.6 +/- 4% of these cells coexpressing CD34. An average of 17.5% of clonogenic hematopoietic progenitors derived from CD45(neg)PFV precursors expressed the retroviral transgene. Addition of serum to cultures after retroviral exposure supported transgene expression in resulting hematopoietic cells derived from hemogenic CD45(neg)PFV precursors. Our study represents the first report to demonstrate that retroviral transduction systems, similar to those used currently in clinical gene therapy protocols, are capable of efficient transduction of hematopoietic progenitors derived from hESCs.

Animals↗
PubMed1997

The integrin very late antigen-4 is expressed in human smooth muscle cell. Involvement of alpha 4 and vascular cell adhesion molecule-1 during smooth muscle cell differentiation.

Vascular cell adhesion molecule-1 (VCAM-1) and its counterreceptor, the integrin very late antigen-4 (VLA-4), have recently been identified in smooth muscle cells during intimal thickening in humans and in newly forming vessels during ontogeny in mice, respectively. We examined the coexpression of VCAM-1 and the alpha 4 integrin subunit in human smooth muscle cells. The expression of VCAM-1 and alpha 4 subunit were studied during development of the aorta. In the 10-week-old human fetal aorta, VCAM-1 and alpha 4 were strongly expressed in smooth muscle cells. Their expression was dramatically reduced within the 24th week of gestation and disappeared in the adult aortic media. However, smooth muscle cells from intimal atherosclerotic thickening of adult aorta reexpressed both VCAM-1 and alpha 4. In a culture model mimicking smooth muscle differentiation, VCAM-1 mRNA and protein and alpha 4 integrin protein were coexpressed with smooth muscle-specific variants of cytoskeletal and contractile proteins, smooth muscle myosin heavy chain, caldesmon heavy chain, and desmin. Treatment with antibodies against VCAM-1 or alpha 4 integrin subunit interfered with the mRNA induction of smooth muscle-specific markers of differentiation. These results in vitro, associated with the transitory expression of VCAM-1 and VLA-4 during vascular ontogeny and the atherosclerosis process, point to a possible role of VCAM-1 and VLA-4 in the induction of smooth muscle differentiation.

Adult↗
PubMedDate not supplied

B-cell differentiation, apoptosis and proliferation in diffuse large B-cell lymphomas.

Diffuse large B-cell lymphomas (DLBCL) represent the most common type of adult non-Hodgkin's lymphomas in Western countries and are characterized by heterogeneous clinical, histological, immunophenotypic and genetic features. Recent investigations using cDNA and oligonucleotide microarrays have identified molecularly distinct groups of DLBCL with respect to the B-cell differentiation gene expression profile: the germinal center (GC) B-cell-like DLBCL, the activated B-cell-like DLBCL and the type 3 DLBCL. The GC B-cell-like DLBCL were characterized by the expression of genes of the normal GC B-cells, the activated B-cell-like DLBCL were characterized by the expression of genes that are normally induced luring in vitro activation of peripheral blood B-cells, while the type 3 DLBCL did not express either set of genes at a high level. Patients with GC B-cell-like DLBCL had more favorable clinical outcome than those with activated B-cell-like or type 3 DLBCL. Immunohistochemical studies have shown that the bc16/CD10/MUM1/CD138 B-cell differentiation immunophenotypes are prognostically relevant and may predict the cDNA classification in a sizable fraction of DLBCL. In the last few years, there has been accumulating molecular and immunohistochemical evidence indicating links between B-cell differentiation gene expression profiles and expression of apoptosis and cell cycle-associated genes in DLBCL. The present review summarizes data with respect to the relationships between B-cell differentiation, apoptosis and proliferation in DLBCL.

Animals↗
PubMed1995

Mitogen-activated protein kinase activation is insufficient for growth factor receptor-mediated PC12 cell differentiation.

When expressed in PC12 cells, the platelet-derived growth factor beta receptor (beta PDGF-R) mediates cell differentiation. Mutational analysis of the beta PDGF-R indicated that persistent receptor stimulation of the Ras/Raf/mitogen-activated protein (MAP) kinase pathway alone was insufficient to sustain PC12 cell differentiation. PDGF receptor activation of signal pathways involving p60c-src or the persistent regulation of phospholipase C gamma was required for PC12 cell differentiation. beta PDGF-R regulation of phosphatidylinositol 3-kinase, the GTPase-activating protein of Ras, and the tyrosine phosphatase, Syp, was not required for PC12 cell differentiation. In contrast to overexpression of oncoproteins involved in regulating the MAP kinase pathway, growth factor receptor-mediated differentiation of PC12 cells requires the integration of other signals with the Ras/Raf/MAP kinase pathway.

Animals↗
PubMed1984

The role of B cell differentiation factors and specific T cell help in the pathogenesis of primary hypogammaglobulinemia.

We have examined the function of T and B cells from patients with late onset primary acquired hypogammaglobulinemia (PHG). T cells from these patients give effective help to normal B cells for antigen-dependent antibody synthesis. PHG mononuclear cells also synthesize normal quantities of B cell differentiation factors, which enhance IgG, IgM and antigen-dependent antibody synthesis by normal lymphocytes. While patient T cells appear to behave appropriately, the responsiveness of patient B cells is abnormal. Although they respond to differentiation factors with increased synthesis of IgM, overall levels are 10-50-fold lower than normal B cells, and they produce little or no IgG. This pattern of response is not altered if normal T cells are the source of help. The poor response of the B cell appears to represent immaturity rather than an inherent defect, as IgG-secreting clones can be obtained after Epstein-Barr virus transformation of lymphocytes from certain patients, and some of these clones respond to differentiation factors with increased IgG production. The lack of any functional defect in the T population, and the apparent immaturity rather than abnormality of the B cells, may implicate accessory cells in the pathogenesis of the disease.

Agammaglobulinemia↗
PubMed1984

[Differential cell growth inhibition and terminal differentiation induction by chemotherapeutic agents of a human acute myelogenous leukemia cell line (HL-60) in vitro].

The relationship between cell growth inhibitory effects and terminal differentiation-inducing effects of nine clinically active chemotherapeutic agents was evaluated using HL-60, a human acute myelogenous leukemia cell line. Continuous exposure to HL-60 cells of adriamycin, daunorubicin, mitoxantrone, m-AMSA, cytosine arabinoside, 6-thioguanine (6-TG), actinomycin-D (Act-D) and vincristine resulted in percentage increase of morphologically differentiated cells and phagocytic cells. Hydrocortisone at a concentration of up to 10(-4) M failed to produce this effect. Examination of actual numbers per flask of morphologically differentiated cells and phagocytic cells revealed, however, that all these agents except Act-D and 6-TG failed to produce a numerical increase in differentiated cells in comparison with those of control groups at day 6. Only Act-D and 6-TG were able to produce increases in the percentage, as well as actual number, of differentiated cells. These data indicate that the percentage increase in terminal differentiation-induced cells by certain chemotherapeutic agents is due not to their ability to increase differentiated cells but to their ability to inhibit the growth of primitive cells preferentially.

Anthraquinones↗
PubMed1992

Overexpression of Mos, Ras, Src, and Fos inhibits mouse mammary epithelial cell differentiation.

Mammary epithelial cells terminally differentiate in response to lactogenic hormones. We present evidence that oncoprotein overexpression is incompatible with this hormone-inducible differentiation and results in striking cellular morphological changes. In mammary epithelial cells in culture, lactogenic hormones (glucocorticoid and prolactin) activated a transfected beta-casein promoter and endogenous beta-casein gene expression. This response to lactogenic hormone treatment was paralleled by a decrease in cellular AP-1 DNA-binding activity. Expression of the mos, ras, or src (but not myc) oncogene blocked the activation of the beta-casein promoter induced by the lactogenic hormones and was associated with the maintenance of high levels of AP-1. Mos expression also increased c-fos and c-jun mRNA levels. Overexpression of Fos and Jun from transiently transfected constructs resulted in a functional inhibition of the glucocorticoid receptor in these mouse mammary epithelial cells. This finding clearly suggests that glucocorticoid receptor inhibition arising from oncogene expression will contribute to the block in hormonally induced mammary epithelial cell differentiation. Expression of Src resulted in the loss of the normal organization and morphological phenotype of mammary epithelial cells in the epithelial/fibroblastic line IM-2. Activation of a conditional c-fos/estrogen receptor gene encoding an estrogen-dependent Fos/estrogen receptor fusion protein also morphologically transformed mammary epithelial cells and inhibited initiation of mammary epithelial differentiation-associated expression of the beta-casein and WDNM 1 genes. In response to estrogen treatment, the cells displayed a high level of AP-1 DNA-binding activity. Our results demonstrate that high cellular AP-1 levels contribute to blocking the ability of mammary epithelial cells in culture to respond to lactogenic hormones. This and other studies indicate that the oncogene products Mos, Ras, and Src exert their effects, at least in part, by stimulating cellular Fos and probably cellular Jun activity.

Animals↗
PubMed2005

sox4b is a key player of pancreatic alpha cell differentiation in zebrafish.

Pancreas development relies on a network of transcription factors belonging mainly to the Homeodomain and basic Helix-Loop-Helix families. We show in this study that, in zebrafish, sox4, a member of the SRY-like HMG-box (SOX) family, is required for proper endocrine cell differentiation. We found that two genes orthologous to mammalian Sox4 are present in zebrafish and that only one of them, sox4b, is strongly expressed in the pancreatic anlage. Transcripts of sox4b were detected in mid-trunk endoderm from the 5-somite stage, well before the onset of expression of the early pancreatic gene pdx-1. Furthermore, by fluorescent double in situ hybridization, we found that expression of sox4b is mostly restricted to precursors of the endocrine compartment. This expression is not maintained in differentiated cells although transient expression can be detected in alpha cells and some beta cells. That sox4b-expressing cells belong to the endocrine lineage is further illustrated by their absence from the pancreata of slow-muscle-omitted mutant embryos, which specifically lack all early endocrine markers while retaining expression of exocrine markers. The involvement of sox4b in cell differentiation is suggested firstly by its up-regulation in mind bomb mutant embryos displaying accelerated pancreatic cell differentiation. In addition, sox4b knock-down leads to a drastic reduction in glucagon expression, while other pancreatic markers including insulin, somatostatin, and trypsin are not significantly affected. This disruption of alpha cell differentiation is due to down-regulation of the homeobox arx gene specifically in the pancreas. Taken together, these data demonstrate that, in zebrafish, sox4b is expressed transiently during endocrine cell differentiation and plays a crucial role in the generation of alpha endocrine cells.

Amino Acid Sequence↗
PubMed1989

Decidualization and insulin-like growth factor (IGF) binding protein: implications for its role in stromal cell differentiation and the decidual cell in haemochorial placentation.

The somatomedins or insulin-like growth factors (IGFs) are polypeptides which are involved in proliferation of a number of cell types and have been implicated in fetal growth and development. Cellular responses to IGFs are mediated via binding to two classes of trans-membrane receptors. However, IGFs also bind with high affinity to binding proteins (IGF-BP) in plasma and other body fluids. In plasma the majority of IGF is associated with a GH-dependent 150 kd IGF-BP whereas a second small mol. wt (29-35 kd) IGF-BP is relatively unsaturated. It is this latter class of IGF-BP which has been demonstrated to be synthesized or secreted by a number of cell types and is detected in body fluids and secretions such as amniotic fluid, cerebrospinal fluid and milk. Although the exact relationship between these binding proteins and their role in IGF action has not been clarified, evidence suggests that the 29-35 kd form may function as an inhibitor and promoter of IGF action. During the menstrual cycle IGF-BP synthesis of this latter class appears associated with stromal fibroblast populations and it is proposed that this is involved in specifying proliferation of this cell type which differentiates into decidual cells. This IGF-BP also represents the major soluble secretory protein of the decidualized endometrium and its component decidual cell, during pregnancy and probably is the major source of the protein in pregnancy, contributing to the amniotic fluid and peripheral serum levels. In this article the implications of local decidual production of IGF-BP is discussed with reference to the thesis that decidualization, which is associated with species exhibiting haemochorial placentation, is involved in regulatory mechanisms of feto-placental development and growth.

Carrier Proteins↗