Loss of Tbx3 in Mouse Eye Causes Retinal Angiogenesis Defects Reminiscent of Human Disease

Invest Ophthalmol Vis Sci. 2023 May 1;64(5):1. doi: 10.1167/iovs.64.5.1.


Purpose: Familial exudative vitreoretinopathy (FEVR) and Norrie disease are examples of genetic disorders in which the retinal vasculature fails to fully form (hypovascular), leading to congenital blindness. While studying the role of a factor expressed during retinal development, T-box factor Tbx3, we discovered that optic cup loss of Tbx3 caused the retina to become hypovascular. The purpose of this study was to characterize how loss of Tbx3 affects retinal vasculature formation.

Methods: Conditional removal of Tbx3 from both retinal progenitors and astrocytes was done using the optic cup-Cre recombinase driver BAC-Dkk3-Cre and was analyzed using standard immunohistochemical techniques.

Results: With Tbx3 loss, the retinas were hypovascular, as seen in patients with retinopathy of prematurity (ROP) and FEVR. Retinal vasculature failed to form the stereotypic tri-layered plexus in the dorsal-temporal region. Astrocyte precursors were reduced in number and failed to form a lattice at the dorsal-temporal edge. We next examined retinal ganglion cells, as they have been shown to play a critical role in retinal angiogenesis. We found that melanopsin expression and Islet1/2-positive retinal ganglion cells were reduced in the dorsal half of the retina. In previous studies, the loss of melanopsin has been linked to hyaloid vessel persistence, which we also observed in the Tbx3 conditional knockout (cKO) retinas, as well as in infants with ROP or FEVR.

Conclusions: To the best of our knowledge, these studies are the first demonstration that Tbx3 is required for normal mammalian eye formation. Together, the results provide a potential genetic model for retinal hypovascular diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Familial Exudative Vitreoretinopathies
  • Humans
  • Infant, Newborn
  • Mammals
  • Mice
  • Retina
  • Retinal Degeneration*
  • Retinal Ganglion Cells
  • Retinal Vessels
  • Retinopathy of Prematurity*
  • T-Box Domain Proteins


  • TBX3 protein, human
  • T-Box Domain Proteins
  • Tbx3 protein, mouse