Ocular developmental defects, like Anophthalmia and Microphthalmia, cause 10% of childhood blindness, yet in many cases the cause is unknown. In cases of bilateral anophthalmia and microphthalmia, the underlying cause has been primarily linked to mutations in two anterior neural patterning transcription factors: Sox2 and Otx2. Anterior neural patterning precedes eye field formation, which gives rises to the neural retina and retinal pigment epithelium progenitors, yet how anterior neural plate patterning is molecularly linked to eye field formation is unknown. Our recent work provides insight into this connection. At the start of anterior neural plate formation in Xenopus laevis, we found expression of T-box transcription factor, Tbx3. Our preliminary data shows that Otx2 directly activates Tbx3 at this stage in vivo. Among all the eye field transcription factors that we have investigated, Tbx3 is the only one involved in both early neural induction and eye field determination. In culture Tbx3 is required to generate neuroepithelium from human embryonic stem cells, however the in vivo role of Tbx3 during early mammalian development has not been studied, in part because null mutations are embryonic lethal. Our preliminary data shows that Tbx3 is required for normal eye formation, since conditional ablation in the optic cup results in a thinner optic nerve and fewer dorsal retinal ganglion cells. Our working hypothesis is that mouse Tbx3 is required even earlier, at the onset of neural induction.
In Aim 1, we will determine when Tbx3 is first required for mouse eye formation by conditionally deleting Tbx3 prior to neural plate formation, and separately, eye field formation. Using Xenopus laevis we will investigate the regulation of Tbx3 during neural induction and eye field determination.
In Aim 2, we will determine how loss of Tbx3 in the optic cup affects the formation of dorsal retinal ganglion, and possibly other retinal cells, in both mouse and frog. Our proposal is in line with NEI?s Programs and Research Priorities on Retinal Disease that states as one of its goals, to ?study the disease pathogenesis and genetic factors that underlie structure, function, and the biology of retinal diseases.? Completion of this R21 will provide an integrated view of the genes linking early neural plate and eye field formation and lead to a better understanding of the signaling pathways that, when altered, result in Anophthalmia and Microphthalmia.

Public Health Relevance

The cause of anophthalmia (no eye) or microphthalmia (small eye) in many cases is unknown because the underlying molecular mechanism driving the initiating steps in eye formation remains to be discovered. We identified T-box transcription factor, Tbx3, as the initiating transcription factor in eye formation in frog. The goals of this proposal are to identify how Tbx3 is switched on and discover how Tbx3 functions in the mouse retina.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Biology of the Visual System Study Section (BVS)
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Araj, Houmam H
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Upstate Medical University
Schools of Medicine
United States
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