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Biomedical subjects

Richard Grose

Publications and source records attributed to Richard Grose.

16 recordsLinked to original sources
PubMed2005

Fibroblast growth factor signaling in tumorigenesis.

Fibroblast growth factors and their signaling receptors have been associated with multiple biological activities, including proliferation, differentiation and motility. Consequently, they have evoked interest as candidate oncogenes with the potential to initiate and/or promote tumorigenesis. This has resulted in a large literature describing the presence of these growth factors and their receptors in cancer cell lines and primary tumors of diverse origin. However, it is only recently that compelling evidence has emerged to implicate the fibroblast growth factors (Fgfs) and their receptors in the genesis of human cancers. Here, we outline the model systems that demonstrate the potential oncogenic nature of Fgf signaling and summarise recent evidence that implicates aberrant Fgf signaling as important in the natural history of some common human cancers.

Animals↗
PubMed2004

Common ground in the transcriptional profiles of wounds and tumors.

Healing wounds and developing tumors are both sites of dynamic interactions between a variety of cell types. Recent microarray studies comparing wounds and tumors have identified characteristic similarities in gene expression that may prove to be useful for assessing cancer prognosis and for choosing subsequent treatment.

Gene Expression Profiling↗
PubMed2004

Fibroblast growth factor receptor 1-IIIb is dispensable for skin morphogenesis and wound healing.

Alternative splicing in the extracellular domain is a characteristic feature of members of the fibroblast growth factor receptor (FGFR) family. This splicing event generates receptor variants, which differ in their ligand binding specificities. A poorly characterized splice variant is FGFR1-IIIb, recently found to be a functional FGF receptor predominantly expressed in the skin. Here we show that FGFR1-IIIb is expressed in normal and wounded mouse skin. Reduced expression of this type of receptor was found in wounds of healing-impaired genetically diabetic mice, suggesting that downregulation of FGFR1-IIIb is associated with wound healing defects. To address this possibility, we deleted the IIIb exon of FGFR1 in mice. The lack of FGFR-IIIb did not alter the expression of either FGFR1-IIIc, other FGF receptor genes or of FGFR1-IIIb ligands in normal and wounded skin. Histological analysis of the skin of FGFR1-IIIb knockout animals did not reveal any obvious abnormalities. Furthermore, full-thickness excisional skin wounds in these mice healed normally and no defects could be observed at the macroscopic or histological level. Finally, several genes that encode key players in wound repair were normally expressed in these animals. These data demonstrate that FGFR1-IIIb is dispensable for skin development and wound repair.

Alternative Splicing↗
PubMed2004

Wound-healing studies in transgenic and knockout mice.

Injury to the skin initiates a cascade of events including inflammation, new tissue formation, and tissue remodeling, that finally lead to at least partial reconstruction of the original tissue. Historically, animal models of repair have taught us much about how this repair process is orchestrated and, over recent years, the use of genetically modified mice has helped define the roles of many key molecules. Aside from conventional knockout technology, many ingenious approaches have been adopted, allowing researchers to circumvent such problems as embryonic lethality, or to affect gene function in a tissue- or temporal-specific manner. Together, these studies provide us with a growing source of information describing, to date, the in vivo function of nearly 100 proteins in the context of wound repair. This article focuses on the studies in which genetically modified mouse models have helped elucidate the roles that many soluble mediators play during wound repair, encompassing the fibroblast growth factor (FGF) and transforming growth factor-beta (TGF-beta) families and also data on cytokines and chemokines. Finally, we include a table summarizing all of the currently published data in this rapidly growing field. For a regularly updated web archive of studies, we have constructed a Compendium of Published Wound Healing Studies on Genetically Modified Mice which is avaialble at http://icbxs.ethz.ch/members/grose/woundtransgenic/home.html.

Animals↗
PubMed2003

E-cadherin controls adherens junctions in the epidermis and the renewal of hair follicles.

E-cadherin is thought to mediate intercellular adhesion in the mammalian epidermis and in hair follicles as the adhesive component of adherens junctions. We have tested this role of E-cadherin directly by conditional gene ablation in the mouse. We show that postnatal loss of E-cadherin in keratinocytes leads to a loss of adherens junctions and altered epidermal differentiation without accompanying signs of inflammation. Overall tissue integrity and desmosomal structures were maintained, but skin hair follicles were progressively lost. Tumors were not observed and beta-catenin levels were not strongly altered in the mutant skin. We conclude that E-cadherin is required for maintaining the adhesive properties of adherens junctions in keratinocytes and proper skin differentiation. Furthermore, continuous hair follicle cycling is dependent on E-cadherin.

Adherens Junctions↗
PubMed2003

Epithelial migration: open your eyes to c-Jun.

Tissue-specific removal of c-jun from epidermal cells in mice leads to a failure of eyelid fusion during embryogenesis and reveals roles for c-Jun in wound repair and tumorigenesis in adult skin. This has provided a definitive test of the in vivo function of AP-1 signalling and shown that EGF signalling is key to all of c-Jun's roles in the epidermis.

Animals↗
PubMed2003

Fibroblast growth factor 22 and its potential role during skin development and repair.

We have isolated, using RT-PCR, a cDNA from mouse skin wounds that encodes fibroblast growth factor (FGF) 22, a recently discovered member of the FGF family, which is closely related to FGF-7 and FGF-10. Transient expression of tagged FGF-22 protein in COS-1 and MCF-7 cells revealed that the protein was present within the cell and at the cell surface but was not apparently released from the cell. Analysis of RNA expression revealed that FGF-22 transcripts were not detected in the developing mouse embryo until day E16.5 and in the adult mouse it was expressed in the brain, tongue, and skin, but not in other tissues examined. After skin injury, FGF-22 mRNA levels were slightly down-regulated within the first 5 days after wounding, but expression increased strongly at the later stages of the repair process. In situ hybridization revealed the presence of FGF-22 mRNA throughout the epidermis and hair follicle keratinocytes of E16.5 embryos, as well as in adult skin and keratinocytes of the hyperthickened wound epithelium. This expression pattern suggests a potential role for FGF-22 in cutaneous development and repair.

Animals↗
PubMed2003

Wound healing in the PU.1 null mouse--tissue repair is not dependent on inflammatory cells.

Damage to neonatal and adult tissues always incites an influx of inflammatory neutrophils and macrophages. Besides clearing the wound of invading microbes, these cells are believed to be crucial coordinators of the repair process, acting both as professional phagocytes to clear wound debris and as a major source of wound growth factor signals. Here we report wound healing studies in the PU.1 null mouse, which is genetically incapable of raising the standard inflammatory response because it lacks macrophages and functioning neutrophils. Contrary to dogma, we show that these "macrophageless" mice are able to repair skin wounds with similar time course to wild-type siblings, and that repair appears scar-free as in the embryo, which also heals wounds without raising an inflammatory response. The growth factor and cytokine profile at the wound site is changed, cell death is reduced, and dying cells are instead engulfed by stand-in phagocytic fibroblasts. We also show that hyperinnervation of the wound site, previously believed to be a consequence of inflammation, is present in the PU.1 null wound, too.

Animals↗
PubMed2003

Regulation of wound healing by growth factors and cytokines.

Cutaneous wound healing is a complex process involving blood clotting, inflammation, new tissue formation, and finally tissue remodeling. It is well described at the histological level, but the genes that regulate skin repair have only partially been identified. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. However, the roles played by endogenous growth factors have remained largely unclear. Initial approaches at addressing this question focused on the expression analysis of various growth factors, cytokines, and their receptors in different wound models, with first functional data being obtained by applying neutralizing antibodies to wounds. During the past few years, the availability of genetically modified mice has allowed elucidation of the function of various genes in the healing process, and these studies have shed light onto the role of growth factors, cytokines, and their downstream effectors in wound repair. This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds. Most importantly, we also report on genetic studies addressing the functions of endogenous growth factors in the wound repair process.

Animals↗
PubMed2003

A crucial role for Fgfr2-IIIb signalling in epidermal development and hair follicle patterning.

To understand the role Fgf signalling in skin and hair follicle development, we analysed the phenotype of mice deficient for Fgfr2-IIIb and its main ligand Fgf10. These studies showed that the severe epidermal hypoplasia found in mice null for Fgfr2-IIIb is caused by a lack of the basal cell proliferation that normally results in a stratified epidermis. Although at term the epidermis of Fgfr2-IIIb null mice is only two to three cells thick, it expresses the classical markers of epidermal differentiation and establishes a functional barrier. Mice deficient for Fgf10 display a similar but less severe epidermal hypoplasia. By contrast, Fgfr2-IIIb-/-, but not Fgf10-/-, mice produced significantly fewer hair follicles, and their follicles were developmentally retarded. Following transplantation onto nude mice, grafts of Fgfr2-IIIb-/- skin showed impaired hair formation, with a decrease in hair density and the production of abnormal pelage hairs. Expression of Lef1, Shh and Bmp4 in the developing hair follicles of Fgfr2-IIIb-/- mice was similar to wild type. These results suggest that Fgf signalling positively regulates the number of keratinocytes needed to form a normal stratified epidermis and to initiate hair placode formation. In addition, Fgf signals are required for the growth and patterning of pelage hairs.

Animals↗
PubMed2002

A role for endogenous glucocorticoids in wound repair.

Exogenous glucocorticoids are known to inhibit wound repair, but the roles and mechanisms of action of endogenous glucocorticoids during the healing process are as yet unknown. Therefore, we wounded mice expressing a DNA-binding-defective mutant version of the glucocorticoid receptor (GR(dim) mice) and also analysed fibroblasts from these animals in vitro. We found a remarkably enlarged granulation tissue with a high fibroblast density in GR(dim) mice. This difference is likely to result from an increased migratory and proliferative capacity of GR(dim) fibroblasts and from elevated expression levels of soluble factors involved in granulation tissue formation in wounds of GR(dim) mice. In spite of the larger granulation tissue seen in early wounds, late wounds appeared normal, most likely due to an enhanced ability of GR(dim) fibroblasts to contract collagen. These results demonstrate an as yet unidentified role of endogenous glucocorticoids in the regulation of wound repair.

Animals↗
PubMed2002

Immediate early genes krox-24 and krox-20 are rapidly up-regulated after wounding in the embryonic and adult mouse.

Embryos show a remarkable capacity for perfect repair after injury. Wounding of embryonic skin triggers rapid activation of epithelial sweeping and mesenchymal contraction tissue movements that bear striking analogy to several naturally occurring morphogenetic tissue movements, but very little is known about the early molecular signals that might initiate such movements. Here, we describe the rapid and transient up-regulation of two immediate early genes, krox-24 and krox-20, after wounding of the embryonic mouse. Furthermore, we demonstrate that these signals are conserved, but of longer duration, in the neonate and adult wound situation. To further test the roles of these transcription factors in vivo, we performed wound healing studies on embryos lacking either Krox-24 or 20. Despite the dramatic up-regulation of these genes in response to injury, our studies reveal that neither of them on their own is essential for repair.

Age Factors↗
PubMed2002

Wound healing recapitulates morphogenesis in Drosophila embryos.

The capacity to repair a wound is a fundamental survival mechanism that is activated at any site of damage throughout embryonic and adult life. To study the cell biology and genetics of this process, we have developed a wounding model in Drosophila melanogaster embryos that allows live imaging of rearrangements and changes in cell shape, and of the cytoskeletal machinery that draws closed an in vivo wound. Using embryos expressing green fluorescent protein (GFP) fusion proteins, we show that two cytoskeletal-dependent elements -- an actin cable and dynamic filopodial/lamellipodial protrusions -- are expressed by epithelial cells at the wound edge and are pivotal for repair. Modulating the activities of the small GTPases Rho and Cdc42 demonstrates that these actin-dependent elements have differing cellular functions, but that either alone can drive wound closure. The actin cable operates as a 'purse-string' to draw the hole closed, whereas filopodia are essential for the final 'knitting' together of epithelial cells at the end of repair. Our data suggest a more complex model for epithelial repair than previously envisaged and highlight remarkable similarities with the well-characterized morphogenetic movement of dorsal closure in Drosophila.

Actins↗
PubMed2002

A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair.

Integrins are ubiquitous transmembrane receptors that play crucial roles in cell-cell and cell-matrix interactions. In this study, we have determined the effects of the loss of beta 1 integrins in keratinocytes in vitro and during cutaneous wound repair. Flow cytometry of cultured beta 1-deficient keratinocytes confirmed the absence of beta 1 integrins and showed downregulation of alpha 6 beta 4 but not of alpha v integrins. beta 1-null keratinocytes were characterised by poor adhesion to various substrates, by a reduced proliferation rate and by a strongly impaired migratory capacity. In vivo, the loss of beta 1 integrins in keratinocytes caused a severe defect in wound healing. beta 1-null keratinocytes showed impaired migration and were more densely packed in the hyperproliferative epithelium. Surprisingly, their proliferation rate was not reduced in early wounds and even increased in late wounds. The failure in re-epithelialisation resulted in a prolonged inflammatory response, leading to dramatic alterations in the expression of important wound-regulated genes. Ultimately, beta 1-deficient epidermis did cover the wound bed, but the epithelial architecture was abnormal. These findings demonstrate a crucial role of beta 1 integrins in keratinocyte migration and wound re-epithelialisation. Movies available on-line

Animals↗