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Review
. 2006 Dec;17(6):726-40.
doi: 10.1016/j.semcdb.2006.10.002. Epub 2006 Oct 27.

An essential role for FGF receptor signaling in lens development

Michael L Robinson  1
Affiliations
Review

An essential role for FGF receptor signaling in lens development

Michael L Robinson. Semin Cell Dev Biol. 2006 Dec.

Abstract

Since the days of Hans Spemann, the ocular lens has served as one of the most important developmental systems for elucidating fundamental processes of induction and differentiation. More recently, studies in the lens have contributed significantly to our understanding of cell cycle regulation and apoptosis. Over 20 years of accumulated evidence using several different vertebrate species has suggested that fibroblast growth factors (FGFs) and/or fibroblast growth factor receptors (FGFRs) play a key role in lens development. FGFR signaling has been implicated in lens induction, lens cell proliferation and survival, lens fiber differentiation and lens regeneration. Here we will review and discuss historical and recent evidence suggesting that (FGFR) signaling plays a vital and universal role in multiple aspects of lens development.

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Figures

Figure 1
Figure 1
(A) Morphological development of the lens begins as the optic vesicle (OV) approaches the presumptive lens ectoderm (PLE). (B) Upon physical contact of the OV with the PLE, cells within the PLE elongate forming the lens placode. (C) The lens placode invaginates forming the lens pit and the OV invaginates forming the optic cup. (D) The lens pit deepens and the connection of the lens pit and overlying surface ectoderm is lost forming the lens vesicle. (E) The overlying surface ectoderm differentiates into the corneal epithelium and the cells at the posterior of the lens vesicle elongate forming the primary fiber cells. (F) The primary fiber cells fill the lumen of the lens vesicle as they reach the anterior lens cells making up the lens epithelium. The inner layer of the optic cup differentiates into the neural retina. (G) The mature lens consists of an anterior epithelial layer composed of non-proliferating central lens epithelial cells (cuboidal cells with white cytoplasm) and a narrow band of proliferating cells known as the germinative zone (pink cells). Just posterior to the germinative zone is the transitional zone (blue cells) where many genes important for fiber cell differentiation are initially expressed. Just posterior to the lens equator (dotted line) transitional zone epithelial cells begin elongating forming secondary fiber cells (green cells). As secondary fiber cells progress through later stages of differentiation, they lose their intracellular organelles (represented by the shrinkage and loss of red nuclei). The lens nucleus (yellow) is composed of fiber cells that were present in the embryonic lens. The mature lens is bathed on the anterior surface by the aqueous humor and on the posterior surface by the vitreous humor. Adapted from Lovicu and McAvoy, 2005 [170]
Figure 2
Figure 2
(A) FGFR molecules typically consist of three extracellular immunoglobulin-like (Ig) domains (I, II, and III, of which domain I may or may not be present), a single transmembrane domain and a split, intracellular tyrosine kinase domain. The use of an alternative exon encoding the carboxyl terminal half of Ig domain 3 is the major determinant of FGF ligand specificity and FGFR1-3 are present in both IIIb (A) and IIIc (B) isoforms. (C, D) Ligand induced dimerization of either FGFR isoform results in trans-autophosphorylation of FGFR monomers as well as phosphorylation of the FGFR associated molecule FRS2, initiating an intracellular signal transduction cascade. (E) Ectopic expression of a membrane bound FGFR lacking an intracellular tyrosine kinase domain inhibits FGFR activity by heterodimerization with wildtype FGFRs. (F) FGFR activity can also be inhibited by the sequestration of extracellular FGF ligands by dimerized secreted FGFRs.
Figure 3
Figure 3
(A) Transgenic expression of secreted FGF1 results in elongation of lens epithelial cells and the induction of immunologically detectable expression of β-crystallins (brown staining, arrowhead). An embryonic day 15 lens from Robinson et al., 1995 [74] is shown. (B) Transgenic expression of a dimerized secreted FGFR3-IIIc led to a postnatal (seven day old eye shown) posterior movement of the transitional zone (arrows), normally present at the lens equator (dotted line) to a region at the back of the lens (arrowhead). From Govindarajan and Overbeek, 2001 [97]. (C) Retroviral transduction of a dominant negative FGFR1 construct in the chick lens was not able to prevent lens fiber cell elongation in a cell autonomous fashion (shown in whole mount). In these experiments, the FGFR1 sequences were separated by the coding sequence for LacZ by an internal ribosome entry site allowing for the identification of transduced cells by X-gal staining. Note that transduced cells appeared both in the lens fibers (black arrowheads) and the lens epithelial cells (white arrowheads). Image modified from Huang et al., 2003 [68]. (D) Conditional deletion of FGFR2 at the lens placode stage led to several lens phenotypes including small size, increased apoptosis, incomplete cell cycle withdrawal of lens fiber cells and fiber cell degeneration [148]. A newborn FGFR2 deficient lens is shown.
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References

    1. Kuszak JR, Costello MJ. The Structure of the Vertebrate Lens. In: Lovicu FJ, Robinson ML, editors. The Structure of the Vertebrate Lens. New York, NY: Cambridge University Press; 2004. pp. 71–118.
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