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Clay Conner, IV, David R. Hyde; Role of Notch Signaling during Photoreceptor Regeneration in Zebrafish. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6654.
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© ARVO (1962-2015); The Authors (2016-present)
Zebrafish regenerate lost photoreceptors from constant intense light treatment. During regeneration, the Müller glial cell reenters the cell cycle to produce neuronal progenitor cells, which continue to divide, migrate to the photoreceptor layer and differentiate into rods and cones. The mechanisms regulating neuronal progenitor cell proliferation and differentiation remain unknown. One signaling pathway associated with these processes during development is Notch-Delta. After the transmembrane Notch receptor binds a ligand, it is cleaved by γ-secretase to release the Notch Intracellular Domain (NICD), which relocates to the nucleus to activate transcription of downstream Notch targets, like her6, which ultimately, regulates cell proliferation and cell fate decisions Identifying and investigating these transcription factors and other regulative genes will allow us to better understand how this signaling pathway plays a role in these regenerative events
We intravitreally injected a γ-secretase inhibitor, Compound E (CE), after 24 hours of constant light treatment. These fish were subsequently injected every 12 hours and maintained in the dark after the initial 24 hours of light treatment. The eyes were collected at various timepoints, were fixed, embedded and cryosectioned. Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to stain the sections for spatial and temporal expression patterns.
CE increased the number of "activated" or proliferating Müller glia and proliferating cells during regeneration relative to DMSO controls, which suggests that Notch signaling may negatively regulate the extent of Müller glia activation and cell proliferation. Furthermore, at 14 days post light treatment (dpl), Müller glia were significantly reduced in number in CE-treated retinas relative to DMSO-injected controls. However, the number of Müller glia appear to recover by 28 dpl. This suggests that Notch signaling is responsible for maintaining Müller glial cell identity during the proliferative events, possibly through lateral inhibition.
Notch signaling most likely controls the reentry of Müller glia into the cell cycle and regulates the amount of cell proliferation during a typical regenerative event. Overall, this suggests a complex process of signaling events that control the extent of Müller glia initiating the proliferation response and the amplification of the number of subsequent neuronal progenitor cells during this regenerative event.
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