title: Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation.
abstract: OBJECTIVE
  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 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.
authors: Department of Surgery, Creighton University, Omaha, Nebraska, USA.
authors: Murali R
authors: MR
authors: Kuracha
authors: Daniel
authors: D
authors: Burgess
authors: Ed
authors: E
authors: Siefker
authors: Jake T
authors: JT
authors: Cooper
authors: Jonathan D
authors: JD
authors: Licht
authors: Michael L
authors: ML
authors: Robinson
authors: Venkatesh
authors: V
authors: Govindarajan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002386:Cataract / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D003315:Cornea / Q000196:embryology* / Q000378:metabolism; D003316:Corneal Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D007908:Lens, Crystalline / Q000196:embryology* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D011247:Pregnancy; D011270:Pregnancy, Animal; D017346:Protein Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse