Notch signaling regulates growth and differentiation in the mammalian lens.
The Notch signal transduction pathway regulates the decision to proliferate versus differentiate. Although there are a myriad of mouse models for the Notch pathway, surprisingly little is known about how these genes regulate early eye development, particularly in the anterior lens. We employed both gain-of-function and loss-of-function approaches to determine the role of Notch signaling in lens development. Here we analyzed mice containing conditional deletion of the Notch effector Rbpj or overexpression of the activated Notch1 intracellular domain during lens formation. We demonstrate distinct functions for Notch signaling in progenitor cell growth, fiber cell differentiation and maintenance of the transition zone. In particular, Notch signaling controls the timing of primary fiber cell differentiation and is essential for secondary fiber cell differentiation. Either gain or loss of Notch signaling leads to formation of a dysgenic lens, which in loss-of-function mice undergoes a profound postnatal degeneration. Our data suggest both Cyclin D1 and Cyclin D2, and the p27(Kip1) cyclin-dependent kinase inhibitor act downstream of Notch signaling, and define multiple critical functions for this pathway during lens development.
Rowan
Sheldon
S
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Conley
Kevin W
KW
Le
Tien T
TT
Donner
Amy L
AL
Maas
Richard L
RL
Brown
Nadean L
NL
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D056742:Cyclin D2; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D007908:Lens, Crystalline / Q000166:cytology / Q000196:embryology*; D051379:Mice; D051881:Receptor, Notch1 / Q000378:metabolism*
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497762:Notch1 protein, mouse; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27