Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation

Murali R. Kuracha, Daniel Burgess, Ed Siefker, Jake T. Cooper, Jonathan D. Licht, Michael L. Robinson, Venkatesh Govindarajan

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 p57KIP2, normally upregulated at the onset of fiber differentiation were prematurely induced in the Spry mutant lens epithelial cells. However, terminal differentiation markers such as β- or γ-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.

Original languageEnglish
Pages (from-to)6887-6897
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number9
DOIs
StatePublished - Aug 2011

Fingerprint

Lenses
Ectoderm
Fibroblast Growth Factors
Differentiation Antigens
Epithelial Cells
Crystallins
Fibroblast Growth Factor 2
Hematoxylin
Eosine Yellowish-(YS)
Transgenes
In Situ Hybridization
Immunohistochemistry
Alleles
Apoptosis
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

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Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation. / Kuracha, Murali R.; Burgess, Daniel; Siefker, Ed; Cooper, Jake T.; Licht, Jonathan D.; Robinson, Michael L.; Govindarajan, Venkatesh.

In: Investigative Ophthalmology and Visual Science, Vol. 52, No. 9, 08.2011, p. 6887-6897.

Research output: Contribution to journalArticle

Kuracha, Murali R. ; Burgess, Daniel ; Siefker, Ed ; Cooper, Jake T. ; Licht, Jonathan D. ; Robinson, Michael L. ; Govindarajan, Venkatesh. / Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation. In: Investigative Ophthalmology and Visual Science. 2011 ; Vol. 52, No. 9. pp. 6887-6897.
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AU - Burgess, Daniel

AU - Siefker, Ed

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AU - Licht, Jonathan D.

AU - Robinson, Michael L.

AU - Govindarajan, Venkatesh

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N2 - 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 p57KIP2, normally upregulated at the onset of fiber differentiation were prematurely induced in the Spry mutant lens epithelial cells. However, terminal differentiation markers such as β- or γ-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.

AB - 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 p57KIP2, normally upregulated at the onset of fiber differentiation were prematurely induced in the Spry mutant lens epithelial cells. However, terminal differentiation markers such as β- or γ-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.

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