Glycogen Synthase Kinase 3 Regulates the Genesis of Displaced Retinal Ganglion Cells3

Glycogen synthase kinase 3 (GSK3) proteins (GSK3 alpha and GSK3 beta) are key mediators of signaling pathways, with crucial roles in coordinating fundamental biological processes during neural development. Here we show that the complete loss of GSK3 signaling in mouse retinal progenitors leads to microphthalmia with broad morphologic defects. A single wild-type allele of either GSK3 alpha or GSK3 beta is able to rescue this phenotype. In this genetic context, all cell types are present in a functional retina. However, we unexpectedly detected a large number of cells in the inner nuclear layer expressing retinal ganglion cell (RGC)-specific markers (called displaced RGCs, dRGCs) when at least one allele of GSK3 alpha is expressed. The excess of dRGCs leads to an increased number of axons projecting into the ipsilateral medial terminal nucleus, an area of the brain belonging to the non-image-forming visual circuit and poorly targeted by RGCs in wild-type retina. Transcriptome analysis and optomotor response assay suggest that at least a subset of dRGCs in Gsk3 mutant mice are direction-selective RGCs. Our study thus uncovers a unique role of GSK3 in controlling the production of ganglion cells in the inner nuclear layer, which correspond to dRGCs, a rare and poorly characterized retinal cell type.

Automated summary

The study reveals a unique role of GSK3 in controlling the production of ganglion cells in the inner nuclear layer, corresponding to dRGCs, a rare and poorly characterized retinal cell type. In Gsk3 mutant mice, an excess of dRGCs leads to more axons projecting into the non-image-forming visual circuit, and at least a subset of dRGCs are direction-selective RGCs.