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Fibroblast growth factor 5 precursor (FGF-5) (Heparin-binding growth factor 5) (HBGF-5) (Smag-82)


Attenuation of FGF signalling in mouse beta-cells leads to diabetes.

Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and [[FGF10]], are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.

MeSH Terms

  • Aging
  • Animals
  • Blood Glucose
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 2
  • Fibroblast Growth Factors
  • Glucose Transporter Type 1
  • Glucose Transporter Type 2
  • Homeodomain Proteins
  • Humans
  • Insulin
  • Islets of Langerhans
  • Mice
  • Mice, Transgenic
  • Monosaccharide Transport Proteins
  • Pancreas
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptors, Fibroblast Growth Factor
  • Signal Transduction
  • Trans-Activators

Plakoglobin suppresses epithelial proliferation and hair growth in vivo.

Plakoglobin regulates cell adhesion by providing a modulatable connection between both classical and desmosomal cadherins and their respective cytoskeletal linker proteins. Both plakoglobin and the related protein beta-catenin are posttranscriptionally upregulated in response to Wnt-1 in cultured cells. Upregulation of beta-catenin has been implicated in potentiating hyperproliferation and tumor formation. To investigate the role of plakoglobin in these functions we expressed a full-length (PG) and an NH(2)-terminally truncated form of plakoglobin (DeltaN80PG) in mouse epidermis and hair follicles, tissues which undergo continuous and easily observed postnatal renewal and remodeling. Expression of these constructs results in stunted hair growth, a phenotype that has also been observed in transgenic mice expressing Wnt3 and Dvl2 (Millar et al. 1999). Hair follicles from PG and DeltaN80PG mice show premature termination of the growth phase (anagen) of the hair cycle, an event that is regulated in part by FGF5 (Hebert et al. 1994). The proliferative rate of the epidermal cells was reduced and apoptotic changes, which are associated with entry into the regressive phase of the hair follicle cycle (catagen), occurred earlier than usual.

MeSH Terms

  • Aging
  • Animals
  • Base Sequence
  • Cell Adhesion Molecules
  • Cell Division
  • Cell Line, Transformed
  • Cytoskeletal Proteins
  • Desmoplakins
  • Desmosomes
  • Epidermal Cells
  • Epidermis
  • Epithelial Cells
  • Hair Follicle
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides
  • Polymerase Chain Reaction
  • Recombinant Proteins
  • Sequence Deletion
  • Transfection
  • gamma Catenin