TBX3 is required for the differentiation of a subset of retinal ganglion and cone photoreceptor cells

Abstract

Retinogenesis is a key step driving the formation of the neurons that later coordinate angiogenesis in the retina. Understanding these complex interactions requires dissecting apart its cellular and molecular drivers. To tease apart 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 retina phenotype observed upon Tbx3 loss most likely stems from a disruption of 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, RXRgamma, ISL1/2, POU4F2, SHH, LHX4 and OTX2) is severely diminished, halting proper RGC and cone differentiation. Utilizing birthdating 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 driver of early RGC formation positions it as a promising new candidate biomarker for early-stage glaucoma diagnosis and potentially therapeutic targeting.