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.

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The initial steps of pattern formation in the developing Drosophila eye involve the coordination of cell cycles, changes in cell shape, and the specification of the R8 photoreceptor cell. These events begin several cell rows ahead of the morphogenetic furrow and are positively regulated by secreted signaling proteins and the proneural HLH transcription factor atonal (ato). Two HLH regulatory proteins that function to suppress neuronal development in other tissues, extra macrochaetae (emc) and hairy (h), are expressed ahead of the morphogenetic furrow. While neither h nor emc is required for photoreceptor cell determination, in emc-h-clones the morphogenetic furrow and differentiated eye field advance up to eight ommatidial rows ahead of adjacent wild-type tissue. This indicates that morphogenetic furrow progression and neuronal differentiation are negatively regulated by a combination of anteriorly expressed HLH regulatory proteins.

CNS progenitors choose a fate, exit mitosis and differentiate. Basic helix-loop-helix (bHLH) transcription factors are key regulators of neurogenesis, but their molecular mechanisms remain unclear. In the mouse retina, removal of the bHLH factor Math5 (Atoh7) causes the loss of retinal ganglion cells (RGCs) and appearance of excess cone photoreceptors. Here, we show a simultaneous requirement for Math5 in retinal neuron formation and cell cycle progression. At embryonic day E11.5, Math5-/- cells are unable to assume the earliest fates, particularly that of an RGC, and instead adopt the last fate as Müller glia. Concurrently, the loss of Math5 causes mitotically active retinal progenitors to undergo aberrant cell cycles. The drastic fate shift of Math5-/- cells correlates with age-specific alterations in p27/Kip1 expression and an inability to become fully postmitotic. Finally, Math5 normally suppresses NeuroD1 within Math5-expressing cells and inhibits Ngn2 expression and cone photoreceptor genesis within separate cell populations. Thus, Math5 orchestrates neurogenesis in multiple ways, regulating both intrinsic and extrinsic processes.