Overlapping effects of different members of the FGF family on lens fiber differentiation in transgenic mice

Development ◽  
1998 ◽  
Vol 125 (17) ◽  
pp. 3365-3377 ◽  
Author(s):  
F.J. Lovicu ◽  
P.A. Overbeek
Keyword(s):  
Epithelial Cells ◽  
Transgenic Mice ◽  
Expression Patterns ◽  
Lens Epithelial Cells ◽  
Developmental Study ◽  
Ocular Development ◽  
Spatial Regulation ◽  
Temporal And Spatial ◽  
Induced Changes ◽  
Downstream Signalling Pathway

Fibroblast growth factors (FGFs), such as FGF-1, have been shown to induce differentiation of lens epithelial cells both in tissue culture and in transgenic mice. In the present study, using the alpha A-crystallin promoter, we generated transgenic mice that express different FGFs (FGF-4, FGF-7, FGF-8, FGF-9) specifically in the lens. All four FGFs induced changes in ocular development. Microphthalmic eyes were evident in transgenic mice expressing FGF-8, FGF-9 and some lines expressing FGF-4. A developmental study of the microphthalmic eyes revealed that, by embryonic day 15, expression of these FGFs induced lens epithelial cells to undergo premature fiber differentiation. In less severely affected lines expressing FGF-4 or FGF-7, the lens epithelial cells exhibited a premature exit from the cell cycle and underwent a fiber differentiation response later in development, leading to cataract formation. The responsiveness of lens cells to different FGFs indicates that these proteins stimulate the same or overlapping downstream signalling pathway(s). These overlapping effects of different FGFs on a common cell type indicate that the normal developmental roles for these genes are determined by the temporal and spatial regulation of their expression patterns. The fact that any of these FGFs can induce ocular defects and loss of lens transparency implies that it is essential for the normal eye to maintain very specific spatial control over FGF expression in order to prevent cataract induction.

scholarly journals Identification of Differential Gene Expression Pattern in Lens Epithelial Cells Derived from Cataractous and Noncataractous Lenses of Shumiya Cataract Rat

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Hidetoshi Ishida ◽  
Teppei Shibata ◽  
Yuka Nakamura ◽  
Yasuhito Ishigaki ◽  
Dhirendra P. Singh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Expression Patterns ◽  
Synergetic Effect ◽  
Gene Expression Pattern ◽  
Lens Opacity ◽  
Lens Epithelial Cells ◽  
Lens Fiber ◽  
Molecular Events ◽  
Old Rats

The Shumiya cataract rat (SCR) is a model for hereditary cataract. Two-thirds of these rats develop lens opacity within 10-11 weeks. Onset of cataract is attributed to the synergetic effect of lanosterol synthase (Lss) and farnesyl-diphosphate farnesyltransferase 1 (Fdft1) mutant alleles that lead to cholesterol deficiency in the lenses, which in turn adversely affects lens biology including the growth and differentiation of lens epithelial cells (LECs). Nevertheless, the molecular events and changes in gene expression associated with the onset of lens opacity in SCR are poorly understood. In the present study, a microarray-based approach was employed to analyze comparative gene expression changes in LECs isolated from the precataractous and cataractous stages of lenses of 5-week-old SCRs. The changes in gene expression observed in microarray results in the LECs were further validated using real-time reverse transcribed quantitative PCR (RT-qPCR) in 5-, 8-, and 10-week-old SCRs. A mild posterior and cortical opacity was observed in 5-week-old rats. Expressions of approximately 100 genes, including the major intrinsic protein of the lens fiber (Mip and Aquaporin 0), deoxyribonuclease II beta (Dnase2B), heat shock protein B1 (HspB1), and crystallin γ (γCry) B, C, and F, were found to be significantly downregulated (0.07-0.5-fold) in rat LECs derived from cataract lenses compared to that in noncataractous lenses (control). Thus, our study was aimed at identifying the gene expression patterns during cataract formation in SCRs, which may be responsible for cataractogenesis in SCR. We proposed that cataracts in SCR are associated with reduced expression of these lens genes that have been reported to be related with lens fiber differentiation. Our findings may have wider implications in understanding the effect of cholesterol deficiency and the role of cholesterol-lowering therapeutics on cataractogenesis.

Changes in lens connexin expression lead to increased gap junctional voltage dependence and conductance

1995 ◽  
Vol 269 (3) ◽  
pp. C590-C600 ◽  
Author(s):  
P. J. Donaldson ◽  
Y. Dong ◽  
M. Roos ◽  
C. Green ◽  
D. A. Goodenough ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Gap Junction ◽  
Voltage Dependence ◽  
Expression Patterns ◽  
Fiber Cell ◽  
Lens Epithelial Cells ◽  
Connexin Expression ◽  
Fiber Cells ◽  
Gap Junctional ◽  
Mouse Lens

The differentiation of mouse lens epithelial cells into fiber cells is a useful model for studying the changes of the electrical properties of gap junction (cell-to-cell) channels that are induced by an alteration in connexin expression patterns. In this model, cuboidal lens epithelial cells differentiate into elongated fiber cells, and the expression of connexin43 (Cx43) in the epithelial cells is replaced with the production of high levels of Cx50 and Cx46 in the fiber cells. We now report a new procedure to isolate mouse lens fiber cell pairs suitable for double whole cell patch-clamp analysis. Analysis was also performed for fiberlike cell pairs differentiated from epithelial cells in culture. Voltage dependence and unitary conductance of fiber cell gap junction channels were determined and compared with the corresponding values previously measured for the channels joining lens epithelial cells and for lens connexin channels formed in Xenopus oocyte pairs. Our results support a differentiation-induced shift toward stronger gap junctional voltage dependence and larger unitary conductances in the fiber cells. Our data further reflect a balanced functional contribution of Cx50 and Cx46 in the fiber cell-to-cell channels rather than a predominance of a single connexin.

Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice

2006 ◽  
Vol 290 (1) ◽  
pp. C282-C289 ◽  
Author(s):  
Shizuya Saika ◽  
Kazuo Ikeda ◽  
Osamu Yamanaka ◽  
Kathleen C. Flanders ◽  
Yoshitaka Ohnishi ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Expression Patterns ◽  
Lens Epithelium ◽  
Lens Epithelial Cells ◽  
Hypodermic Needle ◽  
Rt Pcr ◽  
Mesenchymal Transition ◽  
Adenoviral Gene Transfer

We have examined the effect of adenovirus-mediated expression of bone morphogenic protein-7 (BMP-7) and inhibitors of differentiation 2 and 3 (Id2 and Id3) on injury-induced epithelial-to-mesenchymal transition (EMT) of lens epithelium in mice. Id2 and Id3 are known to be upregulated by BMP-7 and to antagonize Smad2/3 signaling. The Cre-LoxP system adenoviral gene transfer was used. Three microliters of adenoviral solution (2 × 107 PFU/μl) were injected into the right lens of adult male C57BL/6 mice ( n = 144) at the time of capsular injury induced using a hypodermic needle under both general and topical anesthesia. A mixture of Cre-adenovirus (Cre-Ad) and vector encoding mBMP-7, mId2, or mId3 was administered in a test group. Control lenses were treated with Cre-Ad alone. After healing intervals of 5 or 10 days, the animals were killed and then we performed histological processes or RNA extraction from the lens. RT-PCR, real-time RT-PCR, and immunohistochemistry showed expression of each introduced gene in the lens. Exogenous BMP-7 upregulated expression of Id2 and Id3 in injured lenses, and gene introduction of Id2 or Id3 also upregulated BMP-7 expression. Gene transfer of BMP-7, Id2, or Id3 delayed injury-induced EMT of the lens epithelial cells as evaluated by histology and expression patterns of α-smooth muscle actin and collagens in association with reduction of Smad2 COOH-terminal phosphorylation. Gene transfer of BMP-7, Id2, or Id3 delayed injury-induced EMT of lens epithelial cells and subsequent sealing of the capsular break with fibrous tissue in mice.

Microscopic Characterization of Ocular Development and Disease

1999 ◽  
Vol 5 (S2) ◽  
pp. 1080-1081
Author(s):  
J. Potts ◽  
P. Conley ◽  
R. Champion
Keyword(s):  
Epithelial Cells ◽  
Lens Epithelial Cell ◽  
Fiber Formation ◽  
Human Lens ◽  
Lens Epithelial Cells ◽  
Ocular Development ◽  
Fiber Cells ◽  
Growth Activity ◽  
Lens Growth

The embryonic lens contains two populations of cells, lens epithelial cells and lens fiber cells. As the growth of the human lens is linear from the age of 10 to 90, lens epithelial cells divide and differentiate into fiber cells at a uniform rate during adulthood. Any defects that arise during fiber formation will remain in the lens. We postulate that regulation of early lens growth is critical for the onset of cataracts that usually occur later in life. Slowing the growth of the lens could therefore provide a strategy to suppress the formation of cataracts. However, the factor(s) that control lens growth in vivo have not been identified.We have identified 18 receptor and cytoplasmic kinases present in lens epithelial cells. Using these as potential targets for factors controlling growth, we tested corresponding ligands in a lens epithelial cell proliferation assay. Platelet-derived growth factor (PDGF) proved to promote a growth activity similar to, but distinct from, that of embryo serum.

Oxidation-induced changes in human lens epithelial cells

2006 ◽  
Vol 41 (9) ◽  
pp. 1425-1432 ◽  
Author(s):  
Li Huang ◽  
Rosendo Estrada ◽  
Marta C. Yappert ◽  
Douglas Borchman
Keyword(s):  
Epithelial Cells ◽  
Human Lens ◽  
Lens Epithelial Cells ◽  
Human Lens Epithelial Cells ◽  
Induced Changes

Expression of a truncated FGF receptor results in defective lens development in transgenic mice

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 3959-3967 ◽  
Author(s):  
M.L. Robinson ◽  
L.A. MacMillan-Crow ◽  
J.A. Thompson ◽  
P.A. Overbeek
Keyword(s):  
Epithelial Cells ◽  
Transgenic Mice ◽  
Polymerase Chain Reaction Amplification ◽  
Dominant Negative ◽  
Lens Epithelial Cells ◽  
Type I ◽  
Lens Development ◽  
Fgf Receptor ◽  
Surface Receptors ◽  
Normal Lens

Members of the fibroblast growth factor (FGF) family are thought to initiate biological responses through the activation of cell surface receptors which must dimerize to transmit an intracellular signal. Mammalian lens epithelial cells respond to exogenous extracellular FGF, either in tissue culture or in transgenic mice, by initiating fiber cell differentiation. The role of FGF signalling in normal lens development was evaluated by lens-specific synthesis of a kinase-deficient FGF receptor type I (FGFR1) in transgenic mice. This truncated FGF receptor is thought to act as a dominant negative protein by heterodimerization with endogenous FGF receptors. The presence of transgenic mRNA in the lens was confirmed by in situ hybridization and by polymerase chain reaction amplification of reverse transcribed lens RNA (RT-PCR). The presence of transgenic protein was determined by Western blotting with antibodies to an extracellular domain of FGFR1. Three of four transgenic families expressing the truncated FGF receptor exhibited lens defects ranging from cataracts to severe microphthalmia. While the microphthalmic lenses displayed a normal pattern of differentiation-specific crystallin expression, the lens epithelial cells were reduced in number and the lens fiber cells displayed characteristics consistent with the induction of apoptosis. Our results support the view that FGF receptor signalling plays an essential role in normal lens biology.

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