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J. A. Brzezinski, IV, D. Rudolph, L. Prasov, T. Glaser; Notch Signaling in Postmitotic Retinal Neurons Causes a Slow Transdifferentiation to Müller Glial Fate. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5032. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The basic helix-loop-helix transcription factor Math5 (Atoh7) is transiently expressed in a subset of postmitotic retinal precursors during early histogenesis and is necessary for retinal ganglion cell (RGC) formation. Math5 lineage tracing experiments have shown that Math5 is permissive for all retinal cell types, suggesting that additional factors are involved in RGC fate determination. Feedback through the Notch signaling pathway is thought to inhibit RGC formation. Moreover, Notch signaling can inhibit neurogenesis and promote Müller glia formation in proliferating retinal progenitors. Here, we investigate the effects of Notch signaling on Math5+ precursor fate.
We generated Math5-Cre mice that continuously express activated Notch (R26-NICD-ires-nGFP) upon Cre-mediated recombination. We examined the fate of NICD-GFP+ cells at several developmental time-points to test how Notch signaling affects the fate of multipotent postmitotic precursors.
None of the NICD-GFP+ cells, which derive from Math5+ precursors, developed into RGCs. Instead, the entire lineage differentiated into Müller glia. To follow the progression of this fate shift, we examined Math5-Cre retinas from day E15.5 to P21. The NICD-GFP+ cells initially developed into multiple neuron types, including RGCs, and were interspersed across the retina. However, most cells were transformed by day P7 into glia, which were arranged in tight radial clusters. The NICD-GFP+ cells did not re-enter the cell cycle or undergo apoptosis, ruling out clonal expansion of glial cells or selective loss of neurons as alternative mechanisms. A small number of NICD-GFP+ cells in neonatal retinas co-expressed neuronal and glial markers. The presence of these "transition" cells strongly suggests direct transdifferentiation of neurons into glia in these mice.
Our data show that forced Notch signaling in postmitotic cells allows neuronal fate initially, but over time slowly re-programs neurons to transdifferentiate into Müller glia.
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