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N. L. Brown, T. T. Le, K. W. Conley; The Jagged1-Notch Signaling Pathway Is Essential for Mouse Lens Development. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5409.
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The Notch pathway regulates multiple cell processes. We have demonstrated that the canonical Notch pathway is present during lens development via a Jagged1>Notch1/2>Rbpj>Hes1 signal (Rowan et al., submitted). Moreover, the Notch effectors Rbpj and Hes1 are each required for lens progenitor proliferation, as well as fiber cell differentiation (Rowan et al., submitted; Lee et al., 2006). In this study we examined the genetic requirement for the ligand Jagged1 during lens formation.
Le-Cre mice were mated to mice that had critical exons of Jagged1, Notch1, or Rbpj flanked by lox P sequences. Tissue sections were prepared for histological and immunohistochemical examination of eye anatomy, morphology and a variety of lens development markers.
Le-Cre;Jagged1CKO/CKO adult mice had microphthalmia, not present in Le-Cre; Jagged1CKO/+ and Jagged1CKO/CKO mice. These mutants lacked anterior chambers, pupillary openings and a discernable lens. Postnatal day 3 (P3) Le-Cre;Jagged1CKO/+ animals had microphthalmic lenses with abnormal anterior epithelial, transition zone and fiber cell compartments. Le-Cre;Jagged1CKO/CKO mutant phenotypes ranged from lenses with Peter’s Anomaly to nearly absent lenses that contained no anterior epithelium or transition zone but only a few βcrystallin positive cells. This Jagged1 lens phenotype is more severe than those of Le-Cre;Notch1CKO/CKO or Le-Cre;Rbpj CKO/CKO mice.
Jagged1 is expressed broadly in the lens placode, pit and vesicle, but localized to the transition zone and anterior side of lens fiber cells from E14.5 onwards. The phenotype of Le-Cre;Jagged1CKO/CKO mice suggests this ligand transduces multiple signals, which appear to be partitioned between Notch1 and Notch2 receptors. These receptors may also not strictly complex with the transcriptional activator Rbpj within the nucleus, or Jagged1 may have Notch-independent functions.
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