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Jerome E Roger, Elena Braginskaja, Leah Thomas, Anand Swaroop, Muriel Perron; Glycogen Synthase Kinase 3 restrain the genesis of displaced ganglion cells during retinal development.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2595.
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© ARVO (1962-2015); The Authors (2016-present)
Glycogen Synthase Kinase 3 alpha (GSK3a) and beta (GSK3b) are at the crossroad of several signaling pathways and act as molecular switches mediating their output to regulate numerous cellular processes. Several studies have contributed to delineate GSK3 function in central nervous system development. Here, we investigated the function of GSK3 signaling during retinal development.
We generated mice with partial or complete deletion of Gsk3a and Gsk3b floxed alleles using a-Cre mouse line allowing recombination as early as E10.5 in retinal progenitors. The phenotype was evaluated by immunohistochemistry and electroretinogram (ERG). Retinal ganglion cell (RGC) bodies and axonal projections to the brain were tracked using retrograde and anterograde labelling, respectively.
Complete loss of GSK3 in retinal progenitors led to severe morphological defects with progressive death of the pool of proliferative retinal progenitors and lack of neuronal differentiation inducing microphtalmia. In contrast, expression of at least one Gsk3a or one Gsk3b allele led to differentiation of a functional retina. However, further phenotypic analysis revealed the presence of a large number of Brn3a-positive displaced ganglion cells (dRGCs) located in the inner nuclear layer (INL), while only few dRGCs were present in the control retina. Using retrograde labelling, we demonstrated that axons of these cells located in the INL reached the optic nerve supporting their RGC identity. EdU injection at E12.5 demonstrated that dRGCs were born at the same time than orthotopic RGCs (oRGCs) in both Gsk3 mutant mice and controls. At P0, we observed a larger proportion of dRGCs compared to controls. Since the number of oRGC was unchanged in mutant retina, we propose that this dRGCs increase is due to a higher production of dRGC subtype during the early wave of retinogenesis.
Our study identified GSK3 as the first determinant of this rare cell subtype of ganglion cells during early retinal histogenesis. Therefore, our mouse model displaying an important number of dRGCs may offer a powerful system to further study the synaptic connections, brain projections and visual function of this rare type of RGC with yet unknown functions.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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