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Abstract
Damage to the zebrafish retina stimulates resident Müller glia to reprogram, reenter
the cell cycle, divide asymmetrically, and produce neuronal progenitor cells that
amplify and differentiate into the lost neurons. The transition from quiescent to
proliferative Müller glia involves both positive and negative regulators. We previously
demonstrated that the Notch signaling pathway represses retinal regeneration by maintaining
Müller glia quiescence in zebrafish. Here we examine which Notch receptor is necessary
to maintain quiescence. Quantitative RT-PCR and RNA-Seq analyses reveal that notch3
is expressed in the undamaged retina and is downregulated in response to light damage.
Additionally, Notch3 protein is expressed in quiescent Müller glia of the undamaged
retina, is downregulated as Müller glia proliferate, and is reestablished in the Müller
glia. Knockdown of Notch3 is sufficient to induce Müller glia proliferation in undamaged
retinas and enhances proliferation during light damage. Alternatively, knockdown of
Notch1a, Notch1b, or Notch2 decreases the number of proliferating cells during light
damage, suggesting that Notch signaling is also required for proliferation during
retinal regeneration. We also knockdown the zebrafish Delta and Delta-like proteins,
ligands for the Notch receptors, and find that the deltaB morphant possesses an increased
number of proliferating cells in the light-damaged retina. As with Notch3, knockdown
of DeltaB is sufficient to induce Müller glia proliferation in the absence of light
damage. Taken together, the negative regulation of Müller glia proliferation in zebrafish
retinal regeneration is mediated by Notch3 and DeltaB.
[1
]Department of Biological Sciences, Center for Zebrafish Research, and the Center for
Stem Cells and Regenerative Medicine, Galvin Life Science Center University of Notre
Dame Notre Dame Indiana USA