Spry1 and Spry2 Are Necessary for Lens Vesicle Separation and Corneal Differentiation

被引:35
作者
Kuracha, Murali R. [1 ]
Burgess, Daniel [1 ]
Siefker, Ed [1 ]
Cooper, Jake T. [1 ]
Licht, Jonathan D. [2 ]
Robinson, Michael L. [3 ]
Govindarajan, Venkatesh [1 ]
机构
[1] Creighton Univ, Dept Surg, Omaha, NE 68178 USA
[2] Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA
[3] Miami Univ, Dept Zool, Oxford, OH 45056 USA
关键词
TRANSGENIC MICE; FIBER DIFFERENTIATION; DROSOPHILA-SPROUTY; EXPRESSION; MORPHOGENESIS; INDUCTION; HOMOLOG; FAMILY; GROWTH; GENES;
D O I
10.1167/iovs.11-7531
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
PURPOSE. The studies reported here were performed to analyze the roles of Sproutys (Sprys), downstream targets and negative feedback regulators of the fibroblast growth factor (FGF) signaling pathway, in lens and corneal differentiation. METHODS. Spry1 and -2 were conditionally deleted in the lens and corneal epithelial precursors using the Le-Cre transgene and floxed alleles of Spry1 and -2. Alterations in lens and corneal development were assessed by hematoxylin and eosin staining, in situ hybridization, and immunohistochemistry. RESULTS. Spry1 and -2 were upregulated in the lens fibers at the onset of fiber differentiation. FGF signaling was both necessary and sufficient for induction of Spry1 and -2 in the lens fiber cells. Spry1 and -2 single-or double-null lenses failed to separate from the overlying ectoderm and showed persistent keratolenticular stalks. Apoptosis of stalk cells, normally seen during lens vesicle detachment from the ectoderm, was inhibited in Spry mutant lenses, with concomitant ERK activation. Prox1 and p57(KIP2), normally upregulated at the onset of fiber differentiation were prematurely induced in the Spry mutant lens epithelial cells. However, terminal differentiation markers such as beta- or gamma-crystallin were not induced. Corneal epithelial precursors in Spry1 and -2 double mutants showed increased proliferation with elevated expression of Erm and DUSP6 and decreased expression of the corneal differentiation marker K12. CONCLUSIONS. Collectively, the results indicate that Spry1 and -2 (1) through negative modulation of ERKs allow lens vesicle separation, (2) are targets of FGF signaling in the lens during initiation of fiber differentiation and (3) function redundantly in the corneal epithelial cells to suppress proliferation. (Invest Ophthalmol Vis Sci. 2011;52:6887-6897) DOI:10.1167/iovs.11-7531
引用
收藏
页码:6887 / 6897
页数:11
相关论文
共 42 条
[1]   Pax6 activity in the lens primordium is required for lens formation and for correct placement of a single retina in the eye [J].
Ashery-Padan, R ;
Marquardt, T ;
Zhou, XL ;
Gruss, P .
GENES & DEVELOPMENT, 2000, 14 (21) :2701-2711
[2]   Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1 [J].
Basson, M. Albert ;
Watson-Johnson, Judy ;
Shakya, Reena ;
Akbulut, Simge ;
Hyink, Deborah ;
Costantini, Frank D. ;
Wilson, Patricia D. ;
Mason, Ivor J. ;
Licht, Jonathan D. .
DEVELOPMENTAL BIOLOGY, 2006, 299 (02) :466-477
[3]   Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction [J].
Basson, MA ;
Akbulut, S ;
Watson-Johnson, J ;
Simon, R ;
Carroll, TJ ;
Shakya, R ;
Gross, I ;
Martin, GR ;
Lufkin, T ;
McMahon, AP ;
Wilson, PD ;
Costantini, FD ;
Mason, IJ ;
Licht, JD .
DEVELOPMENTAL CELL, 2005, 8 (02) :229-239
[4]  
Blixt Å, 2000, GENE DEV, V14, P245
[5]   Sef and Sprouty expression in the developing ocular lens:: Implications for regulating lens cell proliferation and differentiation [J].
Boros, Jessica ;
Newitt, Peter ;
Wang, Qian ;
McAvoy, John W. ;
Lovicu, Frank J. .
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2006, 17 (06) :741-752
[6]  
Brownell I, 2000, GENESIS, V27, P81, DOI 10.1002/1526-968X(200006)27:2<81::AID-GENE50>3.0.CO
[7]  
2-N
[8]   Activated Ras alters lens and corneal development through induction of distinct downstream targets [J].
Burgess, Daniel ;
Zhang, Yan ;
Siefker, Ed ;
Vaca, Ryan ;
Kuracha, Murali R. ;
Reneker, Lixing ;
Overbeek, Paul A. ;
Govindarajan, Venkatesh .
BMC DEVELOPMENTAL BIOLOGY, 2010, 10
[9]   Differential display of genes expressed at the midbrain-hindbrain junction identifies sprouty2:: An FGF8-inducible member of a family of intracellular FGF antagonists [J].
Chambers, D ;
Medhurst, AD ;
Walsh, FS ;
Price, J ;
Mason, I .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2000, 15 (01) :22-35
[10]   Expression of sprouty2 during early development of the chick embryo is coincident with known sites of FGF signalling [J].
Chambers, D ;
Mason, I .
MECHANISMS OF DEVELOPMENT, 2000, 91 (1-2) :361-364