The distinct roles of TGF-ß 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 TGFßR2 promotes RGC differentiation but attenuates photoreceptor differentiation. Single-cell RNA sequencing analysis showed that TGFßR2 knockout promotes RGC formation by upregulating genes associated with cell proliferation, axon guidance, and RGC subtype specification. TGFßR2 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/TGFßR2 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. Overall design: P0 retinas from Tgfßr2 control (Cre-) and Tgfßr2 knockout (Cre+) mice were isolated and analyzed using scRNA-seq. Sample Multiplexing: 3' v3 CellPlex P5_S1: Tgfßr2 control P5_S2: Tgfßr2 control P7_S3: Tgfßr2 knockout P7_S4: Tgfßr2 knockout