The role of transforming growth factor beta signaling in retinal development

Glaucoma is primarily caused by the loss or degeneration of retinal ganglion cells (RGCs), leading to permanent blindness. Cell replacement is a feasible therapeutic approach since RGCs do not regenerate after injury. Understanding what regulates RGC development provides new recipes for RGC formation. Using double knockout animals, we found that GDF-15 is the stronger regulator than GDF-11 and Smad2 in RGC differentiation. Deletion of TGFR2 promotes RGC differentiation but attenuates photoreceptor differentiation. Single-cell RNA sequencing analysis showed that TGFR2 knockout promotes RGC formation by upregulating genes associated with cell proliferation, axon guidance, and RGC subtype specification. TGFR2 knockout reduces photoreceptor differentiation and delays its maturation by promoting the expression of apoptotic genes and decreasing the photoreceptor developmental genes. The roles of GDF-11/TGFR2 signaling in photoreceptor differentiation were further confirmed in human retinal organoids. These findings provide insight into the mechanisms of retinal cell development and potential recipes for RGC differentiation. P0 Retinas of the wildtype and Tgfr2 knockout mice were isolated and analyzed using scRNA-seq