Tbx3 controls retinal angiogenesis by driving retinogenesis

Retinal angiogenesis relies on a tightly coordinated sequence of retinogenesis, astrocyte migration, and vascular growth. Understanding this complex system requires dissecting apart its cellular and molecular drivers. To dissect the molecular links coupling retinogenesis to vascular development, we utilized conditional knockout mouse models to selectively delete the transcription factor T-box 3 (Tbx3) in 1) astrocytes, 2) postnatal retinal ganglion cells (RGCs), or 3) retinal progenitors. We demonstrate that the hypovascular phenotype observed in progenitor mutants most likely stems from a disruption in early retinogenesis. Embryonic analyses revealed that TBX3 is required during a critical retinogenic window coinciding with ATOH7 activity. While ATOH7+ progenitors are more abundant in Tbx3 mutants, the expression of key RGC and cone precursor factors (including TBX5, RXRɣ, ISL1/2, POU4F2, SHH, LHX4 and OTX2) is severely diminished, halting proper RGC and cone differentiation. Utilizing birth dating experiments and developmental immunostaining, we establish TBX3 as a novel upstream regulator of RGC and cone photoreceptor specification. Because the degeneration of RGCs is the definitive hallmark of diseases like glaucoma, identifying TBX3 as a master driver of early RGC formation positions it as a promising new candidate biomarker for early-stage glaucoma diagnosis and therapeutic targeting.