title: Sprouty gain of function disrupts lens cellular processes and growth by restricting RTK signaling.
abstract: Sprouty proteins function as negative regulators of the receptor tyrosine kinase (RTK)-mediated Ras/Raf/MAPK pathway in many varied physiological and developmental processes, inhibiting growth factor-induced cellular proliferation, migration and differentiation. Like other negative regulators, Sprouty proteins are expressed in various organs during development, including the eye; ubiquitously expressed in the optic vesicle, lens pit, optic cup and lens vesicle. Given the synexpression of different antagonists (e.g, Sprouty, Sef, Spred) in the developing lens, to gain a better understanding of their specific role, in particular, their ability to regulate ocular growth factor signaling in lens cells, we characterized transgenic mice overexpressing Sprouty1 or Sprouty2 in the eye. Overexpression of Sprouty in the lens resulted in reduced lens and eye size during ocular morphogenesis, influenced by changes to the lens epithelium, aberrant fiber cell differentiation and compromised de novo maintenance of the lens capsule. Here we demonstrate an important inhibitory role for Sprouty in the regulation of lens cell proliferation and fiber differentiation in situ, potentially through its ability to modulate FGF- (and even EGF-) mediated MAPK/ERK1/2 signaling in lens cells. Whilst growth factor regulation of lens cell proliferation and fiber differentiation are required for orchestrating lens morphogenesis and growth, in turn, antagonists such as Sprouty are just as important for regulating the intracellular signaling pathways driving lens cellular processes.
authors.affiliation: Discipline of Anatomy and Histology, Bosch Institute, University of Sydney, NSW, Australia.
authors.forename: Eun Hae
authors.initials: EH
authors.lastname: Shin
authors.affiliation: Discipline of Anatomy and Histology, Bosch Institute, University of Sydney, NSW, Australia.
authors.forename: Guannan
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Discipline of Anatomy and Histology, Bosch Institute, University of Sydney, NSW, Australia.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Discipline of Anatomy and Histology, Bosch Institute, University of Sydney, NSW, Australia; Save Sight Institute, University of Sydney, NSW, Australia. Electronic address: frank.lovicu@sydney.edu.au.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lovicu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006652:Histological Techniques; D007908:Lens, Crystalline / Q000166:cytology / Q000196:embryology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D001973:Bromodeoxyuridine
keywords: EGF; ERK1/2; FGF; Lens development; RTK antagonists; Sprouty