Biomedical subjects

C Dickson

Publications and source records attributed to C Dickson.

At least 19 recordsLinked to original sources

PubMed2005

Accelerated re-epithelialization in beta3-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling.

The upregulation of TGF-beta1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking beta(3)-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-beta1 and enhanced dermal fibroblast infiltration into wounds of beta(3)-null mice. Specifically, beta(3)-integrin deficiency is associated with elevated TGF-beta receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-beta1-mediated dermal fibroblast migration. These data indicate that alpha(v)beta(3)-integrin can suppress TGF-beta1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-beta1 regulation by beta(3)-integrins.

Animals↗

PubMed2004

Requirement for fibroblast growth factor 10 or fibroblast growth factor receptor 2-IIIb signaling for cecal development in mouse.

Epithelial-mesenchymal interactions are critical for the formation of gastrointestinal buds such as the cecum from the midgut, but the mechanisms regulating this process remain unclear. To investigate this problem, we have studied the temporal and spatial expression of key genes known to orchestrate branching morphogenesis. At E10.5, Fibroblast growth factor 10 (Fgf10) is specifically expressed in the mesenchyme above the future cecal epithelial bud, whereas Fgfr2b is found throughout the gut epithelium. From E11.5 onwards, Fgf10 expression is found throughout the cecum mesenchyme. Other relevant signaling molecules such as Sonic hedgehog, Wnt2b, and Tbx4 transcripts are found throughout the gut epithelium, including the cecum. Epithelial expression is also seen for Sprouty2, but only from E14.5 onwards. By contrast, Bone morphogenetic 4 (Bmp4) and Pitx2 are specifically expressed in the mesenchyme of the cecal bud at E11.5. Abrogation of either Fgf10 or Fgfr2b leads to similar phenotypes characterized by an arrest of epithelial invasion into the cecal mesenchymal tissue. However, a bud of undifferentiated cecal mesenchymal tissue is maintained throughout development. Our results further indicate that mesenchymal FGF10 acts mostly through the epithelial FGFR2b receptor; thereby triggering invasion of the midgut epithelium into the adjacent mesenchyme via an increased rate of epithelial proliferation at the tip of the cecum. Thus, FGF10 signaling via FGFR2b appears to be critical in the extension of the epithelium into the mesenchyme during cecal development.

Actins↗

PubMed2001

SOX6 binds CtBP2 to repress transcription from the Fgf-3 promoter.

Fgf-3 is expressed in a complex pattern during mouse development. Previously, an essential regulatory element PS4A was identified in the promoter region, and shown to bind at least three factors. To identify the transcription factor(s), we used a yeast one-hybrid screen and obtained a novel Sox6 cDNA (SOX6D). When introduced into cells it strongly repressed activity from both an Fgf-3 reporter gene as well as an artificial promoter containing three PS4A elements. In situ hybridisation analysis showed that Sox6 and Fgf-3 are co-expressed in the otic vesicle of E9.5 mouse embryos in a mutually exclusive pattern, consistent with a repression of Fgf-3 transcription by SOX6. To characterise additional factor(s) involved in Fgf-3 gene repression, a yeast two-hybrid screen was used with the N-terminal portion of SOX6D. Mouse CtBP2 cDNA clones were isolated and shown to bind SOX6 in yeast and mammalian cells. Furthermore, mutational analysis of SOX6 showed that binding to CtBP2, and its responsiveness to this co-repressor, were dependent on a short amino acid sequence motif PLNLSS. Co-expression studies in NIH3T3 cells showed that SOX6 and CtBP2 co-operate to repress activity from the Fgf-3 promoter through the enhancer element PS4A. These results show that SOX6 can recruit CtBP2 to repress transcription from the Fgf-3 promoter.

Alcohol Oxidoreductases↗

PubMed2001

Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb.

Mice deficient for fibroblast growth factor (Fgf)R2-IIIb show a block in thymic growth after embryonic day 12.5, a stage that just precedes its detection in thymic epithelial cells. Fgf7 and Fgf10, the main ligands for FgfR2-IIIb, are expressed in the mesenchyme surrounding the thymic epithelial primordium, and Fgf10-deficient mice also exhibit impaired thymic growth. Hence, Fgf signaling is essential for thymic epithelial proliferation. In addition to the proliferative block, most thymic epithelial cells fail to progress from an immature cytokeratin 5-positive to a cytokeratin 5-negative phenotype. Nevertheless, sufficient epithelial cell differentiation occurs in the severely hypoplastic thymus to allow the development of CD4/CD8-double-positive thymocytes and a very small number of single-positive thymocytes expressing TCRs.

Animals↗

PubMed2001

A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes.

Intercellular signaling by fibroblast growth factors plays vital roles during embryogenesis. Mice deficient for fibroblast growth factor receptors (FgfRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, as well as profound defects in membranous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Here we show that a heterozygotic abrogation of FgfR2-exon 9 (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. The consequences are neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome patients.

Acrocephalosyndactylia↗

PubMed2001

Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4.

Mice deficient for FgfR2-IIIb were generated by placing translational stop codons and an IRES-LacZ cassette into exon IIIb of FgfR2. Expression of the alternatively spliced receptor isoform, FgfR2-IIIc, was not affected in mice deficient for the IIIb isoform. FgfR2-IIIb(-/-) (lac)(Z) mice survive to term but show dysgenesis of the kidneys, salivary glands, adrenal glands, thymus, pancreas, skin, otic vesicles, glandular stomach, and hair follicles, and agenesis of the lungs, anterior pituitary, thyroid, teeth, and limbs. Detailed analysis of limb development revealed an essential role for FgfR2-IIIb in maintaining the AER. Its absence did not prevent expression of Fgf8, Fgf10, Bmp4, and Msx1, but did prevent induction of Shh and Fgf4, indicating that they are downstream targets of FgfR2-IIIb activation. In the absence of FgfR2-IIIb, extensive apoptosis of the limb bud ectoderm and mesenchyme occurs between E10 and E10.5, providing evidence that Fgfs act primarily as survival factors. We propose that FgfR2-IIIb is not required for limb bud initiation, but is essential for its maintenance and growth.

Animals↗

PubMed2001

Differential cyclin D1 requirements of proliferating Schwann cells during development and after injury.

Neurons regulate Schwann cell proliferation, but little is known about the molecular basis of this interaction. We have examined the possibility that cyclin D1 is a key regulator of the cell cycle in Schwann cells. Myelinating Schwann cells express cyclin D1 in the perinuclear region, but after axons are severed, cyclin D1 is strongly upregulated in parallel with Schwann cell proliferation and translocates into Schwann cell nuclei. During development, cyclin D1 expression is confined to the perinuclear region of proliferating Schwann cells and the analysis of cyclin D1-null mice indicates that cyclin D1 is not required for this type of Schwann cell proliferation. As in the adult, injury to immature peripheral nerves leads to translocation of cyclin D1 to Schwann cell nuclei and injury-induced proliferation is impaired in both immature and mature cyclin D1-deficient Schwann cells. Thus, our data indicate that the molecular mechanisms regulating proliferation of Schwann cells during development or activated by axonal damage are fundamentally different.

Aging↗

PubMed2001

The utility of the VCS clip for creation of vascular access for hemodialysis: long-term results and intraoperative benefits.

UNLABELLED: The purpose of this study was to compare the effectiveness of the VCS vascular clip approximating system for the creation of hemodialysis access fistulas. 173 new vascular accesses were created, 92 prosthetic grafts and 81 autologous fistulas over a 40-month period. 50 sutured and 42 clipped fistulas comprised the prosthetic graft series, and 33 sutured and 48 clipped cases the autologous series. Risk factors associated with access patency were correlated and the primary patencies compared in the suture versus clipped group. A significant improvement in primary patency was noted for the clipped prosthetic group at all time points studied, with a positive trend also noted for clipped autologous fistulae. CONCLUSIONS: The vascular clipping system (the VCS system) provides both long-term and immediate advantages for vascular access construction. Clips have been used successfully to treat seven consecutive patients with upper extremity arterial steal syndrome without the technical difficulties associated with traditional methods of repair.

Adult↗

PubMed2001

The psychopathology of bulimic women who report childhood sexual abuse: the mediating role of core beliefs.

Although reported sexual abuse in childhood is associated with bulimic behaviors, less is known about the cognitive factors that explain this association. This study examined the potential role of core beliefs as a mediator in the abuse-bulimia link. Sixty-one bulimic women were interviewed regarding any history of childhood sexual abuse and completed measures of bulimic behaviors, dissociation, depression, and core beliefs. The 21 women who reported a history of childhood sexual abuse had significantly higher levels of several core beliefs and greater levels of psychopathology. Different core beliefs acted as mediators in the relationships between sexual abuse and individual symptoms. The findings support the suggestion that schema-focused cognitive therapy may be useful in working with bulimics, particularly if they have been sexually abused in childhood. Further research is needed to determine the role of core beliefs in mediating the impact of other forms of trauma and how traumas relate to other "escape" behaviors.

Adult↗

PubMed2001

NoBP, a nuclear fibroblast growth factor 3 binding protein, is cell cycle regulated and promotes cell growth.

Secreted and nuclear forms of fibroblast growth factor 3 (FGF3) have opposing effects on cells. The secreted form stimulates cell growth and transformation, while the nuclear form inhibits DNA synthesis and cell proliferation. By using the yeast two-hybrid system we have identified a nucleolar FGF3 binding protein (NoBP) which coimmunoprecipitated and colocalized with FGF3 in transfected COS-1 cells. Characterization of the NoBP binding domain of FGF3 exactly matched the sequence requirements of FGF3 for its translocation into the nucleoli, suggesting that NoBP might be the nucleolar binding partner of FGF3 essential for its nucleolus localization. Carboxyl-terminal domains of NoBP contain linear nuclear and nucleolar targeting motifs which are capable of directing a heterologous protein beta-galactosidase to the nucleus and the nucleoli. While NoBP expression was detected in all analyzed proliferating established cell lines, NoBP transcription was rapidly downregulated in the promyelocytic leukemia cell line HL60 when induced to differentiate. Analysis on the expression pattern of NoBP mRNA throughout the cell cycle in HeLa cells synchronized by lovastatin demonstrated a substantial upregulation during the late G(1)/early S phase. NoBP overexpression conferred a proliferating effect onto NIH 3T3 cells and can counteract the inhibitory effect of nuclear FGF3, suggesting a role of NoBP in controlling proliferation in cells. We propose that NoBP is the functional target of nuclear FGF3 action.

3T3 Cells↗

PubMed2001

Fibroblast growth factor signalling in mouse mammary gland development.

Fibroblast growth factors (Fgfs) and their receptors are important intercellular signalling molecules involved in many aspects of animal development. The aberrant expression of the Fgfs or the inappropriate activation of their cell surface receptors have been implicated in tumorigenesis. Here, we describe the evidence that as well as playing a critical role in the formation of the mammary primordia during embryogenesis, signalling by Fgfs is necessary for optimal lobuloalveolar development of the mouse mammary gland during pregnancy.

Animals↗

PubMed2000

FGF/FGFR-2(IIIb) signaling is essential for inner ear morphogenesis.

Interactions between FGF10 and the IIIb isoform of FGFR-2 appear to be crucial for the induction and growth of several organs, particularly those that involve budding morphogenesis. We determined their expression patterns in the inner ear and analyzed the inner ear phenotype of mice specifically deleted for the IIIb isoform of FGFR-2. FGF10 and FGFR-2(IIIb) mRNAs showed distinct, largely nonoverlapping expression patterns in the undifferentiated otic epithelium. Subsequently, FGF10 mRNA became confined to the presumptive cochlear and vestibular sensory epithelia and to the neuronal precursors and neurons. FGFR-2(IIIb) mRNA was expressed in the nonsensory epithelium of the otocyst that gives rise to structures such as the endolymphatic and semicircular ducts. These data suggest that in contrast to mesenchymal-epithelial-based FGF10 signaling demonstrated for other organs, the inner ear seems to depend on paracrine signals that operate within the epithelium. Expression of FGF10 mRNA partly overlapped with FGF3 mRNA in the sensory regions, suggesting that they may form parallel signaling pathways within the otic epithelium. In addition, hindbrain-derived FGF3 might regulate otocyst morphogenesis through FGFR-2(IIIb). Targeted deletion of FGFR-2(IIIb) resulted in severe dysgenesis of the cochleovestibular membraneous labyrinth, caused by a failure in morphogenesis at the otocyst stage. In addition to the nonsensory epithelium, sensory patches and the cochleovestibular ganglion remained at a rudimentary stage. Our findings provide genetic evidence that signaling by FGFR-2(IIIb) is critical for the morphological development of the inner ear.

Animals↗

PubMed2000

Fibroblast growth factor (FGF) receptor 1-IIIb is a naturally occurring functional receptor for FGFs that is preferentially expressed in the skin and the brain.

Fibroblast growth factors (FGFs) transmit their signals through four transmembrane receptors that are designated FGFR1-4. Alternative splicing in the extracellular region of FGFR1-3 generates receptor variants with different ligand binding affinities. Thus two types of transmembrane receptors (IIIb and IIIc isoforms) have been identified for FGFR2 and FGFR3, and the existence of analogous variants has been postulated for FGFR1 based on its genomic structure. However, only a single full-length transmembrane FGFR1 variant (FGFR1-IIIc) has been identified so far. Here we describe the cloning of a full-length cDNA encoding FGFR1-IIIb from a mouse skin wound cDNA library. This receptor isoform was expressed at the highest levels in a subset of sebaceous glands of the skin and in neurons of the hippocampus and the cerebellum. FGFR1-IIIb was expressed in L6 rat skeletal muscle myoblasts and used in cross-linking and receptor binding studies. FGF-1 was found to bind the receptor with high affinity, whereas FGF-2, -10, and -7 bound with significantly lower affinities. Despite their apparently similar but low affinities, FGF-10 but not FGF-7 induced the activation of p44/42 mitogen-activated protein kinase in FGFR1-IIIb-expressing L6 myoblasts and stimulated mitogenesis in these cells, demonstrating that this new receptor variant is a functional transmembrane receptor for FGF-10.

Amino Acid Sequence↗

PubMed2000

Cysteine-rich fibroblast growth factor receptor alters secretion and intracellular routing of fibroblast growth factor 3.

Expression of the cysteine-rich fibroblast growth factor (FGF) receptor (CFR) in COS-1 cells strongly inhibits the secretion of co-expressed FGF3. By using a column retention assay and affinity chromatography, we demonstrate that at physiological salt concentrations FGF3 binds with strong affinity to CFR in vivo and in vitro. Furthermore, to show that FGF3 binds to CFR in vivo, truncation mutants of CFR with changed subcellular distributions were shown to cause a similar redistribution of FGF3. Although CFR is a 150-kDa integral membrane glycoprotein that is primarily located in the Golgi apparatus, we show here that in COS-1 cells a substantial proportion of CFR is secreted. This is due to a carboxyl-terminal proteolytic cleavage that releases the intraluminal portion of the protein for secretion. However, the apparent size of the integral membrane and secreted CFR appears similar, since the loss of protein mass is balanced by a gain of complex carbohydrates. The released CFR is associated with the extracellular matrix through its affinity for glycosaminoglycans. These findings show that CFR can modulate the secretion of FGF3 and may control its biological activity by regulating its secretion.

Animals↗

PubMed2000

Tyrosine kinase signalling in breast cancer: fibroblast growth factors and their receptors.

The fibroblast growth factors [Fgfs (murine), FGFs (human)] constitute a large family of ligands that signal through a class of cell-surface tyrosine kinase receptors. Fgf signalling has been associated in vitro with cellular differentiation as well as mitogenic and motogenic responses. In vivo, Fgfs are critical for animal development, and some have potent angiogenic properties. Several Fgfs have been identified as oncogenes in murine mammary cancer, where their deregulation is associated with proviral insertions of the mouse mammary tumour virus (MMTV). Thus, in some mammary tumours of MMTV-infected mouse strains, integration of viral genomic DNA into the somatic DNA of mammary epithelial cells was found to have caused the inappropriate expression of members of this family of growth factors. Although examination of human breast cancers has shown an altered expression of FGFs or of their receptors in some tumours, their role in the causation of breast disease is unclear and remains controversial.

Animals↗

PubMed2000

Fibroblast growth factor 9 secretion is mediated by a non-cleaved amino-terminal signal sequence.

Fibroblast growth factors are a family of intercellular signaling molecules with multiple and varied roles in animal development. Most are exported from cells by means of a classical amino-terminal signal sequence that is cleaved from the mature protein during its passage through the secretory pathway. Fibroblast growth factor-9 (Fgf-9) does not contain a recognizable signal sequence, although it is efficiently secreted. In this study, we show that Fgf-9 enters the endoplasmic reticulum and traverses the Golgi complex in a similar manner to other constitutively secreted proteins. Deletion and point mutation analysis has revealed an atypical non-cleaved signal sequence within the amino-terminal region of Fgf-9. Moreover, the first 28 amino acids of Fgf-9 can function as an efficient non-cleaved signal peptide when appended to the amino terminus of green fluorescent protein.

Amino Acid Sequence↗

PubMed2000

Mammary gland oncogenes as indicators of pathways important in mammary gland development.

The identification of dominant acting proto-oncogenes in mammary tumors from mice and humans has highlighted a number of signal transduction pathways that have subsequently been shown to have a role in normal mammary growth and differentiation. Here we describe the use of two different transgenic mouse strategies to investigate the function of two of these signalling pathways in the normal growth and differentiation of the mouse mammary gland during pregnancy.

Animals↗

PubMed2000

Fibroblast growth factor signalling and cyclin D1 function are necessary for normal mammary gland development during pregnancy. A transgenic mouse approach.

A number of growth factors, growth factor receptors and cell cycle regulatory proteins have been implicated in the genesis of mammary carcinomas both in animal models as well as in human breast tumour samples. Studies on the development of the mammary gland has revealed that several of the proto-oncogenes, or their closely related gene-family members, have a function in the normal growth and differentiation of the gland. In this review the role of fibroblast growth factor signalling and the critical requirement for the cell cycle regulator, cyclin D1 is discussed with respect to their normal function in mammary gland development and abnormal role in mammary carcinogenesis.

Animals↗