A thyroid hormone receptor that is required for the development of green cone photoreceptors

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Abstract

Color vision is facilitated by distinct populations of cone photoreceptors in the retina. In rodents, cones expressing different opsin photopigments are sensitive to middle (M, 'green') and short (S, 'blue') wavelengths, and are differentially distributed across the retina1,2. The mechanisms that control which opsin is expressed in a particular cone are poorly understood2,3, but previous in vitro studies implicated thyroid hormone in cone differentiation4,5. Thyroid hormone receptor β2 (TRβ2) is a ligand-activated transcription factor that is expressed in the outer nuclear layer of the embryonic retina6,7. Here we delete Thrb (encoding Trβ2) in mice, causing the selective loss of M-cones and a concomitant increase in S-opsin immunoreactive cones. Moreover, the gradient of cone distribution is disturbed, with S-cones becoming widespread across the retina. The results indicate that cone photoreceptors throughout the retina have the potential to follow a default S-cone pathway and reveal an essential role for Trβ2 in the commitment to an M-cone identity. Our findings raise the possibility that Thrb mutations may be associated with human cone disorders8.

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Figure 1: Targeted disruption of the Trβ2 exon.
Figure 2: Expression of Trβ2 in eye development.
Figure 3: Absence of M-cones and altered distribution of S-cones from Trβ2-deficient mice.
Figure 4: Loss of M-opsin mRNA and premature expression of S-opsin.
Figure 5: Defective cone responses in Trβ2-deficient mice.

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Acknowledgements

We thank J. Nathans for opsin antibodies; C. Stewart for W9.5 ES cells; W. Wood for TrβcDNAs, A.F. Parlow for reagents for TSH studies; I. Lisoukov for assistance with hormone assays; and the ES Cell Facility at the Department of Human Genetics, Mount Sinai School of Medicine, and the Transgenic Facility at the Karolinska Institute for assistance. This work was supported in part by grants from the National Institutes of Health (D.F., J.B.H., T.A.R.), the Swedish Medical Research Council and Swedish Cancer Fund (B.V) and by the Human Frontiers Science Program (D.F., B.V.).

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Correspondence to Thomas A. Reh or Douglas Forrest.

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