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Eleanor R. Trousdale, Jerome E. Roger, Keerthi Ranganath, Anand Swaroop; Gsk3β Regulates Ganglion Cell Differentiation During Mouse Retinal Development. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6014.
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Signaling pathways play an important role in cell fate determination, often by modulating the phosphorylation state of the regulators. Glycogen Synthase Kinase 3 beta (GSK3β) is a key protein kinase involved in the regulation of many biological functions including cell division, proliferation, motility, and apoptosis. This study aims to determine the role of GSK3β in mammalian retinal development.
Gsk3b-floxed mice were mated with Rx-Cre mice to delete Gsk3b in early retinal progenitors. Histological changes were evaluated by immunohistochemistry (IHC) and quantified by cell counting. Changes in gene expression were assessed by qPCR.
The lamination of the retina in Gsk3b-/- is identical to wild type mice. The number of rhodopsin-positive cells is not affected by the lack of Gsk3b. In contrast, Muller cells are activated (GFAP positive), with displaced cell bodies in the inner nuclear layer (INL) as shown with Sox-9 staining. Interestingly, an increase (around 12%) in the number of Brn3a- and NF L-positive cells is observed in the INL, suggesting that they correspond to displaced ganglion cells (GC). However there is no difference in the number of Brn3a positive cells found in the ganglion cell layer (GCL). At E12.5, more GC are already differentiated in Gsk3b-/- mice. By qPCR, GFAP activation is confirmed and suggests that the retina is under stress. Although expression of Nrl, Nr2e3, Rorb and Crx is not altered, several phototransduction genes (e.g. Cngb3, Gnat1, Gnat2) are down regulated, suggesting a potential alteration of photoreceptor function in Gsk3b-/- mice.
We demonstrate that the lack of Gsk3b expression leads to Muller cell activation, and altered ganglion cell differentiation. However, it appears that Gsk3a can compensate for Gsk3b. We are currently generating Gsk3a and b double-knockout mice to fully decipher the function of Gsk3 in retinal development.
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