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Exploring the role of fibroblast growth factor (FGF) signaling in mouse lens fiber differentiation through tissue-specific disruption of FGF receptor gene family

Zhao, Haotian
http://rave.ohiolink.edu/etdc/view?acc_num=osu1072722841

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
The vertebrate lens provides an excellent model to study mechanisms of cell cycle regulation and differentiation. Lens is composed of proliferative epithelium covering the anterior hemisphere and a core of postmitotic fiber cells that are differentiated from the epithelial cells at the lens equator. However, relatively little is known about the identity of molecules in the ocular environment that promote fiber differentiation in vivo. Despite circumstantial evidence suggesting the importance of Fibroblast Growth Factor (FGF) signaling in lens development, its role during lens development in vivo is still unclear and controversial. FGFs act through binding and activation of FGF receptors (FGFRs). The mouse lens expresses at least 3 different FGFR genes (Fgfr1-3) in a dynamic spatio-temporal fashion. In this study, we examined the role of FGF receptor signaling in lens fiber differentiation by targeting Fgfrs individually or in different combinations. To address the role of Fgfr1 and Fgfr2, null mutations of which cause early embryonic lethality prior to ocular induction, in lens development, we performed chimeric analysis and tissue-specific gene inactivation. To achieve lens-specific gene ablation, a transgenic mouse line, MLR10, was generated using this modified alphaA-crystallin promoter that drives Cre recombinase expression in a lens-specific manner from embryonic days 10.5 (E10.5). Our analyses showed that lens fiber differentiation was not prevented in the absence of any single Fgfr. Given the possibility of redundancy among different Fgfrs during lens fiber differentiation, we proceeded to inactivate Fgfrs in different combinations. Histological and gene expression analyses indicated that lens fiber differentiation was intact in all double Fgfr mutants. However, profound lens defects were observed in mice lacking all three Fgfrs. Lens-specific inactivation of Fgfrs causes abnormal proliferation, reduced expression of cell cycle inhibitors p27kip1 and p57kip2 and transcription factor Prox1, misexpression of E-cadherin and increased apoptosis. Moreover, deficiency in FGF signaling suppressed alpha-, beta- and gamma-crystallin expression through downregulation of transcription factor c-Maf and misexpression of Pax6. Consequently, mutant lens cells failed to polarize and elongate properly, forming a hollow lens. Our study demonstrated that FGF signaling integrates cell cycle regulation with differentiation pathways to establish polarized lens structure in vivo.
Michael Rbinson (Advisor)
215 p.
Biology, Genetics
lens development; lens epithelium; lens fiber; differentiation; cell cycle; proliferation; Pax6; c-Maf; FGF; receptor tyrosine kinase; transgenic; conditional knockout

Recommended Citations

Citations

  • Zhao, H. (2004). Exploring the role of fibroblast growth factor (FGF) signaling in mouse lens fiber differentiation through tissue-specific disruption of FGF receptor gene family [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1072722841

    APA Style (7th edition)

  • Zhao, Haotian. Exploring the role of fibroblast growth factor (FGF) signaling in mouse lens fiber differentiation through tissue-specific disruption of FGF receptor gene family. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1072722841.

    MLA Style (8th edition)

  • Zhao, Haotian. "Exploring the role of fibroblast growth factor (FGF) signaling in mouse lens fiber differentiation through tissue-specific disruption of FGF receptor gene family." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1072722841

    Chicago Manual of Style (17th edition)

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© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
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