The question of how cell fates are initially specified and then stably maintained during subsequent terminal differentiation is of fundamental importance to understanding both normal developmental progression and disease mechanisms that transform or destabilize cell fates. Whereas signaling mechanisms and molecules that specify individual cell fates have been studied extensively, much less is known either about the pathways and interactions that maintain these fates stably or about the timing and extent to which different cell states become locked in as terminal differentiation proceeds. The goal of this proposal is to elucidate the genetic mechanisms that stabilize photoreceptor cell fate in the developing Drosophila visual system. The fly retina provides a superbly tractable and well-defined experimental model, with a proven track record in uncovering novel genetic mechanisms that are broadly conserved across species. In particular, the stereotyped patterning and architecture of the fly retina facilitates the identification and tracking of indiviual cell types over space and time, and the wealth of available markers permits detailed assessment of cell fates. Because signaling mechanisms have proven to be extraordinarily conserved, our identification of molecular networks and interactions that stabilize retinal cell fates in the fly are likely to be relevant to mammalian development. Thus our work studying dedifferentiation and transdifferentiation of Drosophila retinal neurons may identify conserved signaling mechanisms that could eventually be harnessed to repair human tissues damaged by degenerative disease or catastrophic injury.
Aim 1 will explore the genetic requirement for the Abelson nonreceptor tyrosine kinase in maintaining the terminally differentiated state of Drosophila photoreceptor neurons. We will test the hypothesis that Abl is required to stabilize photoreceptor fate and define the developmental window in which its function is required. We will ask whether Abl interacts with its canonical signaling partners in this context, or whether it acts through novel mechanisms.
Aim 2 will explore the hypothesis that Abelson-mediated inhibition of Notch signaling is critical for maintenance of photoreceptor fate. Experiments will investigate the contribution of ectopic Notch signaling to loss of neuronal marker expression in Abl mutants, and will assess the sufficiency of ectopic activation of Notch signaling to induce neuronal dedifferentiation in the retina.
Aim 3 will investigate the signaling mechanisms that stabilize/destabilize photoreceptor fates during terminal differentiation. Using a combination of candidate gene approaches and genetic screens, we will identify the genetic circuitries that interact with Abl and Notch signaling to stabilize cell fates in the retina. We will explore whethe analogous signaling mechanisms similarly stabilize/destabilize cell fates in other tissues.
The combination of unsurpassed genetic tractability, the stereotyped organization of the tissue, and the fundamental conservation of developmental signaling mechanisms, makes the Drosophila retina an ideal model system in which to elucidate the molecular mechanisms that maintain the stability of specified retinal cell fates. Because the signaling molecules and networks we are studying have conserved functions in mammals, the discoveries resulting from our investigations will improve understanding of both normal human development and of disease mechanisms that transform or destabilize cell fates.
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