Regulation of vertebrate retinal development by the Notch signaling pathway

The vertebrate central nervous system is composed of a highly diverse set of cell types. One of the great challenges and goals of developmental biology is to elucidate the extrinsic and intrinsic cues that direct an undifferentiated progenitor or stem cell towards a specific cell fate. The retina is an attractive region of the nervous system to study the mechanisms of cell fate determination since it is a relatively simple tissue consisting of a fairly manageable number of cell types (7 major cell types). Notch is a single-pass transmembrane receptor involved in the development of virtually every tissue studied to date from Drosophila to humans. Studies in the nervous system have revealed an important role for Notch signaling in blocking differentiation, and in particular neuronal differentiation. More recently, it has been appreciated that Notch signaling can also promote particular cell fates, namely the glial cell fate. In other studies, Notch activity maintained cells in a non dividing state with neuroepithelial morphology.; Two major questions regarding the role of Notch activity in the developing CNS are (1) what is the requirement for Notch activity in glial cell formation and neuronal subtype specification and (2) how can Notch activity differentially promote glial features and an undifferentiated state? We hypothesize that Notch activity can induce multiple effects during development in a context-dependent manner. In this thesis, we test this hypothesis by asking what cellular and molecular consequences result from inactivating and prolonging Notch activity at different timepoints during mouse retinal development.; Notch1 was found to be essential for proper proliferation, morphology and cellular diversification. Prolonging Notch activity in retinal progenitor cells led cells from an early progenitor program to a later progenitor program to stem cell and glial cell features. Introduction of Notch into a postmitotic population of retinal cells could promote glial features without promoting progenitor or stem cell features. Notch was also found to specifically inhibit the photoreceptor fate and was capable of participating with a positive bHLH to promote an interneuron cell fate. Finally, Notch retinal mutants were used to enrich and identify novel transcripts expressed in developing and mature cone photoreceptor cells and temporally restricted progenitors.