title: Genetic epistasis between heparan sulfate and FGF-Ras signaling controls lens development.
abstract: Vertebrate lens development depends on a complex network of signaling molecules to coordinate cell proliferation, migration and differentiation. In this study, we have investigated the role of heparan sulfate in lens specific signaling by generating a conditional ablation of heparan sulfate modification genes, Ndst1 and Ndst2. In this mutant, N-sulfation of heparan sulfate was disrupted after the lens induction stage, resulting in reduced lens cell proliferation, increased cell death and defective lens fiber differentiation in later lens development. The loss of Ndst function also prevented the assembly of Fgf/Fgfr complexes on the lens cell surface and disrupted ERK signaling within the lens. We further demonstrated that Ndst mutation completely inhibited the FGF1 and Fgf3 overexpression phenotypes, but Kras reactivation was sufficient to reverse the Ndst deficient lens differentiation defect. The epistatic relationship between Ndst and FGF-Ras signaling demonstrates that FGF signaling is the predominant signaling pathway controlled by Ndst in lens development.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Qu
authors.forename: Kristina
authors.initials: K
authors.lastname: Hertzler
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Kay
authors.initials: K
authors.lastname: Grobe
authors.forename: Michael L
authors.initials: ML
authors.lastname: Robinson
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D004843:Epistasis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005346:Fibroblast Growth Factors / Q000235:genetics*; D006497:Heparan Sulfate / Q000235:genetics*; D007908:Lens, Crystalline / Q000201:enzymology / Q000254:growth & development*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000581:Amidohydrolases; D048049:Extracellular Signal-Regulated MAP Kinases; D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D017468:Receptors, Fibroblast Growth Factor; D015238:Sulfotransferases; D018631:ras Proteins; C491855:Ndst2 protein, mouse; C021350:heparitin sulfotransferase