Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Feb 1;101(3):625–634. doi: 10.1172/JCI1360

Lens-specific expression of transforming growth factor beta1 in transgenic mice causes anterior subcapsular cataracts.

Y Srinivasan 1, F J Lovicu 1, P A Overbeek 1
PMCID: PMC508606  PMID: 9449696

Abstract

Transgenic mice were generated by microinjection of a construct containing a self-activating human TGF-beta1 cDNA driven by the lens-specific alphaA-crystallin promoter. Seven transgenic founder mice were generated, and four transgenic lines expressing TGF-beta1 were characterized. By postnatal day 21, mice from the four families exhibited anterior subcapsular cataracts. The lenses in these mice developed focal plaques of spindle-shaped cells that expressed alpha-smooth muscle actin, and that resembled the plaques seen in human anterior subcapsular cataracts. Transgenic mice showed additional ocular defects, including corneal opacification and structural changes in the iris and ciliary body. The corneal opacities were associated with increased exfoliation of the squamous layer of the corneal epithelium and increased DNA replication in the basal epithelium.

Full Text

The Full Text of this article is available as a PDF (887.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arrick B. A., Lopez A. R., Elfman F., Ebner R., Damsky C. H., Derynck R. Altered metabolic and adhesive properties and increased tumorigenesis associated with increased expression of transforming growth factor beta 1. J Cell Biol. 1992 Aug;118(3):715–726. doi: 10.1083/jcb.118.3.715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brunner A. M., Marquardt H., Malacko A. R., Lioubin M. N., Purchio A. F. Site-directed mutagenesis of cysteine residues in the pro region of the transforming growth factor beta 1 precursor. Expression and characterization of mutant proteins. J Biol Chem. 1989 Aug 15;264(23):13660–13664. [PubMed] [Google Scholar]
  3. Connor T. B., Jr, Roberts A. B., Sporn M. B., Danielpour D., Dart L. L., Michels R. G., de Bustros S., Enger C., Kato H., Lansing M. Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye. J Clin Invest. 1989 May;83(5):1661–1666. doi: 10.1172/JCI114065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cousins S. W., McCabe M. M., Danielpour D., Streilein J. W. Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci. 1991 Jul;32(8):2201–2211. [PubMed] [Google Scholar]
  5. Derynck R. TGF-beta-receptor-mediated signaling. Trends Biochem Sci. 1994 Dec;19(12):548–553. doi: 10.1016/0968-0004(94)90059-0. [DOI] [PubMed] [Google Scholar]
  6. Dudley A. T., Lyons K. M., Robertson E. J. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev. 1995 Nov 15;9(22):2795–2807. doi: 10.1101/gad.9.22.2795. [DOI] [PubMed] [Google Scholar]
  7. Font R. L., Brownstein S. A light and electron microscopic study of anterior subcapsular cataracts. Am J Ophthalmol. 1974 Dec;78(6):972–984. doi: 10.1016/0002-9394(74)90811-3. [DOI] [PubMed] [Google Scholar]
  8. Fromm L., Shawlot W., Gunning K., Butel J. S., Overbeek P. A. The retinoblastoma protein-binding region of simian virus 40 large T antigen alters cell cycle regulation in lenses of transgenic mice. Mol Cell Biol. 1994 Oct;14(10):6743–6754. doi: 10.1128/mcb.14.10.6743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gentry L. E., Webb N. R., Lim G. J., Brunner A. M., Ranchalis J. E., Twardzik D. R., Lioubin M. N., Marquardt H., Purchio A. F. Type 1 transforming growth factor beta: amplified expression and secretion of mature and precursor polypeptides in Chinese hamster ovary cells. Mol Cell Biol. 1987 Oct;7(10):3418–3427. doi: 10.1128/mcb.7.10.3418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Green W. R., McDonnell P. J. Opacification of the posterior capsule. Trans Ophthalmol Soc U K. 1985;104(Pt 7):727–739. [PubMed] [Google Scholar]
  13. Hales A. M., Chamberlain C. G., McAvoy J. W. Cataract induction in lenses cultured with transforming growth factor-beta. Invest Ophthalmol Vis Sci. 1995 Jul;36(8):1709–1713. [PubMed] [Google Scholar]
  14. Hales A. M., Schulz M. W., Chamberlain C. G., McAvoy J. W. TGF-beta 1 induces lens cells to accumulate alpha-smooth muscle actin, a marker for subcapsular cataracts. Curr Eye Res. 1994 Dec;13(12):885–890. doi: 10.3109/02713689409015091. [DOI] [PubMed] [Google Scholar]
  15. Helbig H., Kittredge K. L., Coca-Prados M., Davis J., Palestine A. G., Nussenblatt R. B. Mammalian ciliary-body epithelial cells in culture produce transforming growth factor-beta. Graefes Arch Clin Exp Ophthalmol. 1991;229(1):84–87. doi: 10.1007/BF00172268. [DOI] [PubMed] [Google Scholar]
  16. Jampel H. D., Roche N., Stark W. J., Roberts A. B. Transforming growth factor-beta in human aqueous humor. Curr Eye Res. 1990 Oct;9(10):963–969. doi: 10.3109/02713689009069932. [DOI] [PubMed] [Google Scholar]
  17. Knisely T. L., Bleicher P. A., Vibbard C. A., Granstein R. D. Production of latent transforming growth factor-beta and other inhibitory factors by cultured murine iris and ciliary body cells. Curr Eye Res. 1991 Aug;10(8):761–771. doi: 10.3109/02713689109013870. [DOI] [PubMed] [Google Scholar]
  18. Liu J., Hales A. M., Chamberlain C. G., McAvoy J. W. Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor beta. Invest Ophthalmol Vis Sci. 1994 Feb;35(2):388–401. [PubMed] [Google Scholar]
  19. Luo G., Hofmann C., Bronckers A. L., Sohocki M., Bradley A., Karsenty G. BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev. 1995 Nov 15;9(22):2808–2820. doi: 10.1101/gad.9.22.2808. [DOI] [PubMed] [Google Scholar]
  20. Lutty G., Ikeda K., Chandler C., McLeod D. S. Immunohistochemical localization of transforming growth factor-beta in human photoreceptors. Curr Eye Res. 1991 Jan;10(1):61–74. doi: 10.3109/02713689109007611. [DOI] [PubMed] [Google Scholar]
  21. Lyons R. M., Gentry L. E., Purchio A. F., Moses H. L. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol. 1990 Apr;110(4):1361–1367. doi: 10.1083/jcb.110.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Massagué J. TGFbeta signaling: receptors, transducers, and Mad proteins. Cell. 1996 Jun 28;85(7):947–950. doi: 10.1016/s0092-8674(00)81296-9. [DOI] [PubMed] [Google Scholar]
  23. Millan F. A., Denhez F., Kondaiah P., Akhurst R. J. Embryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo. Development. 1991 Jan;111(1):131–143. doi: 10.1242/dev.111.1.131. [DOI] [PubMed] [Google Scholar]
  24. Mishima H., Nakamura M., Murakami J., Nishida T., Otori T. Transforming growth factor-beta modulates effects of epidermal growth factor on corneal epithelial cells. Curr Eye Res. 1992 Jul;11(7):691–696. doi: 10.3109/02713689209000742. [DOI] [PubMed] [Google Scholar]
  25. Montesano R., Orci L. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4894–4897. doi: 10.1073/pnas.85.13.4894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nishida K., Sotozono C., Adachi W., Yamamoto S., Yokoi N., Kinoshita S. Transforming growth factor-beta 1, -beta 2 and -beta 3 mRNA expression in human cornea. Curr Eye Res. 1995 Mar;14(3):235–241. doi: 10.3109/02713689509033520. [DOI] [PubMed] [Google Scholar]
  27. Novotny G. E., Pau H. Myofibroblast-like cells in human anterior capsular cataract. Virchows Arch A Pathol Anat Histopathol. 1984;404(4):393–401. doi: 10.1007/BF00695223. [DOI] [PubMed] [Google Scholar]
  28. Ohta M., Greenberger J. S., Anklesaria P., Bassols A., Massagué J. Two forms of transforming growth factor-beta distinguished by multipotential haematopoietic progenitor cells. Nature. 1987 Oct 8;329(6139):539–541. doi: 10.1038/329539a0. [DOI] [PubMed] [Google Scholar]
  29. Overbeek P. A., Chepelinsky A. B., Khillan J. S., Piatigorsky J., Westphal H. Lens-specific expression and developmental regulation of the bacterial chloramphenicol acetyltransferase gene driven by the murine alpha A-crystallin promoter in transgenic mice. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7815–7819. doi: 10.1073/pnas.82.23.7815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pasquale L. R., Dorman-Pease M. E., Lutty G. A., Quigley H. A., Jampel H. D. Immunolocalization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 in the anterior segment of the human eye. Invest Ophthalmol Vis Sci. 1993 Jan;34(1):23–30. [PubMed] [Google Scholar]
  31. Pelton R. W., Saxena B., Jones M., Moses H. L., Gold L. I. Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol. 1991 Nov;115(4):1091–1105. doi: 10.1083/jcb.115.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Qian S. W., Kondaiah P., Roberts A. B., Sporn M. B. cDNA cloning by PCR of rat transforming growth factor beta-1. Nucleic Acids Res. 1990 May 25;18(10):3059–3059. doi: 10.1093/nar/18.10.3059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Quintas PZ, Leung WC, Mishra SR, Sciulli F, Arroyo C, Bachmann KT, Blair RE, Foudas C, King BJ, Lefmann WC. Measurement of Lambda QCD from nu micro-Fe nonsinglet structure functions at the Fermilab Tevatron. Phys Rev Lett. 1993 Aug 30;71(9):1307–1310. doi: 10.1103/PhysRevLett.71.1307. [DOI] [PubMed] [Google Scholar]
  34. Rafferty N. S. Experimental cataract and wound healing in mouse lens. Invest Ophthalmol. 1973 Feb;12(2):156–160. [PubMed] [Google Scholar]
  35. Reneker L. W., Silversides D. W., Patel K., Overbeek P. A. TGF alpha can act as a chemoattractant to perioptic mesenchymal cells in developing mouse eyes. Development. 1995 Jun;121(6):1669–1680. doi: 10.1242/dev.121.6.1669. [DOI] [PubMed] [Google Scholar]
  36. Robinson M. L., Overbeek P. A., Verran D. J., Grizzle W. E., Stockard C. R., Friesel R., Maciag T., Thompson J. A. Extracellular FGF-1 acts as a lens differentiation factor in transgenic mice. Development. 1995 Feb;121(2):505–514. doi: 10.1242/dev.121.2.505. [DOI] [PubMed] [Google Scholar]
  37. Sanford L. P., Ormsby I., Gittenberger-de Groot A. C., Sariola H., Friedman R., Boivin G. P., Cardell E. L., Doetschman T. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development. 1997 Jul;124(13):2659–2670. doi: 10.1242/dev.124.13.2659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sato Y., Tsuboi R., Lyons R., Moses H., Rifkin D. B. Characterization of the activation of latent TGF-beta by co-cultures of endothelial cells and pericytes or smooth muscle cells: a self-regulating system. J Cell Biol. 1990 Aug;111(2):757–763. doi: 10.1083/jcb.111.2.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schmitt-Gräff A., Pau H., Spahr R., Piper H. M., Skalli O., Gabbiani G. Appearance of alpha-smooth muscle actin in human eye lens cells of anterior capsular cataract and in cultured bovine lens-forming cells. Differentiation. 1990 Apr;43(2):115–122. doi: 10.1111/j.1432-0436.1990.tb00437.x. [DOI] [PubMed] [Google Scholar]
  40. Shah M., Foreman D. M., Ferguson M. W. Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci. 1994 May;107(Pt 5):1137–1157. doi: 10.1242/jcs.107.5.1137. [DOI] [PubMed] [Google Scholar]
  41. Sporn M. B., Roberts A. B. A major advance in the use of growth factors to enhance wound healing. J Clin Invest. 1993 Dec;92(6):2565–2566. doi: 10.1172/JCI116868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Suzuki A., Shioda N., Maeda T., Tada M., Ueno N. A mouse TGF-beta type I receptor that requires type II receptor for ligand binding. Biochem Biophys Res Commun. 1994 Feb 15;198(3):1063–1069. doi: 10.1006/bbrc.1994.1151. [DOI] [PubMed] [Google Scholar]
  43. Suzuki A., Shioda N., Maeda T., Tada M., Ueno N. Cloning of an isoform of mouse TGF-beta type II receptor gene. FEBS Lett. 1994 Nov 21;355(1):19–22. doi: 10.1016/0014-5793(94)01156-7. [DOI] [PubMed] [Google Scholar]
  44. Taketo M., Schroeder A. C., Mobraaten L. E., Gunning K. B., Hanten G., Fox R. R., Roderick T. H., Stewart C. L., Lilly F., Hansen C. T. FVB/N: an inbred mouse strain preferable for transgenic analyses. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2065–2069. doi: 10.1073/pnas.88.6.2065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Uga S. Wound healing in the mouse lens. Exp Eye Res. 1981 Feb;32(2):175–186. doi: 10.1016/0014-4835(81)90006-3. [DOI] [PubMed] [Google Scholar]
  46. Wahl S. M., Hunt D. A., Wakefield L. M., McCartney-Francis N., Wahl L. M., Roberts A. B., Sporn M. B. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788–5792. doi: 10.1073/pnas.84.16.5788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wrana J. L., Attisano L., Wieser R., Ventura F., Massagué J. Mechanism of activation of the TGF-beta receptor. Nature. 1994 Aug 4;370(6488):341–347. doi: 10.1038/370341a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES