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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wang, Y. et al. A locus control region adjacent to the human red and green visual pigment genes. Neuron 9, 429– 440 (1992).
Szel, A., Lukats, A., Fekete, T., Szepessy, Z. & Rohlich, P. Photoreceptor distribution in the retinas of subprimate mammals. J. Opt. Soc. Am. A. Opt. Image Sci. Vis. 17 , 568–579 (2000).
Cepko, C.L., Austin, C.P., Yang, X., Alexiades, M. & Ezzeddine, D. Cell fate determination in the vertebrate retina. Proc. Natl. Acad. Sci. USA 93, 589– 595 (1996).
Kelley, M.W., Turner, J.K. & Reh, T.A. Ligands of steroid/thyroid receptors induce cone photoreceptors in vertebrate retina. Development 121, 3777 –3785 (1995).
Kelley, M.W., Turner, J.K. & Reh, T.A. Regulation of proliferation and photoreceptor differentiation in fetal human retinal cell cultures. Invest. Ophthalmol. Vis. Sci. 36, 1280–1289 ( 1995).
Hodin, R.A. et al. Identification of a thyroid hormone receptor that is pituitary-specific . Science 244, 76–78 (1989).
Sjöberg, M., Vennström, B. & Forrest, D. Thyroid hormone receptors in chick retinal development: differential expression of mRNAs for α and N-terminal variant β receptors. Development 114, 39– 47 (1992).
Newell, F.W. & Diddie, K.R. Typical monochromacy, congenital deafness, and resistance to intracellular action of thyroid hormone. Klin. Monatsbl. Augenheilkd. 171, 731– 734 (1977).
Wood, W.M., Ocran, K.W., Gordon, D.F. & Ridgway, E.C. Isolation and characterization of mouse complementary DNAs encoding α and β thyroid hormone receptors from thyrotrope cells: the mouse pituitary-specific β2 isoform differs at the amino terminus from the corresponding species from rat pituitary tumor cells. Mol. Endocrinol. 5, 1049–1061 (1991).
Ng, L., Forrest, D., Haugen, B.R., Wood, W.M. & Curran, T. LN-Terminal variants of thyroid hormone receptor β: differential function and potential contribution to syndrome of resistance to thyroid hormone. Mol. Endocrinol. 9, 1202–1213 (1995).
Sjöberg, M. & Vennström, B. Ligand-dependent and -independent transactivation by thyroid hormone receptor β2 is determined by the structure of the hormone response element. Mol. Cell. Biol. 15, 4718–4726 ( 1995).
Langlois, M.-F. et al. A unique role of the β-2 thyroid hormone receptor isoform in negative regulation by thyroid hormone. J. Biol. Chem. 272, 24927–24933 (1997).
Bradley, D.J., Towle, H.C. & Young, W.S. III α and β thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in vivo. Proc. Natl. Acad. Sci. USA 91, 439–443 ( 1994).
Forrest, D. et al. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor β: evidence for tissue-specific modulation of receptor function. EMBO J. 15, 3006– 3015 (1996).
Forrest, D., Sjöberg, M. & Vennström, B. Contrasting developmental and tissue-specific expression of α and β thyroid hormone receptor genes. EMBO J. 9, 1519–1528 ( 1990).
Szel, A., Rohlich, P., Mieziewska, K., Aguirre, G. & van Veen, T. Spatial and temporal differences between the expression of short- and middle-wave sensitive cone pigments in the mouse retina: a developmental study. J. Comp. Neurol. 331, 564–577 (1993).
Rohlich, P., van Veen, T. & Szel, A. Two different visual pigments in one retinal cone cell . Neuron 13, 1159–1166 (1994).
Szel, A., van Veen, T. & Rohlich, P. Retinal cone differentiation. Nature 370, 336 (1994).
Lyubarsky, A.L., Falsini, B., Pennesi, M.E., Valentini, P. & Pugh, E.N. Jr., UV- and midwave-sensitive cone-driven retinal responses of the mouse: a possible phenotype for coexpression of cone photopigments. J. Neurosci. 19, 442–455 (1999).
Chiu, M.I. & Nathans, J. A sequence upstream of the mouse blue visual pigment gene directs blue cone-specific transgene expression in mouse retinas. Vis. Neurosci. 11, 773– 780 (1994).
Abel, E.D. et al. Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system. J. Clin. Invest. 104, 291–300 (1999).
Rüsch, A., Erway, L., Oliver, D., Vennström, B. & Forrest, D. Thyroid hormone receptor β-dependent expression of a potassium conductance in inner hair cells at the onset of hearing. Proc. Natl. Acad. Sci. USA 95, 15758– 15762 (1998).
Sjöberg, M. Expression and Function of Chicken Thyroid Hormone Receptors Thesis, Karolinska Institute (1994).
Browman, H.I. & Hawryshyn, C.W. The developmental trajectory of ultraviolet photosensitivity in rainbow trout is altered by thyroxine. Vision Res. 34, 1397–1406 (1994).
Dacey, D.M. Parallel pathways for spectral coding in primate retina. Annu. Rev. Neurosci. 23, 743–775 (2000).
Refetoff, S., Weiss, R.E. & Usala, S.J. The syndromes of resistance to thyroid hormone. Endocrine Rev. 14, 348–399 (1993).
Akhmedov, N.B. et al. A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc. Natl. Acad. Sci. USA 97, 5551–5556 ( 2000).
Haider, N.B. et al. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nature Genet. 24, 127–131 ( 2000).
Chomez, P. et al. Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbA(α) orphan receptor. Development 127, 1489–1498 ( 2000).
Göthe, S. et al. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth and bone maturation . Genes Dev. 13, 1329–1341 (1999).
Bayer, A. et al. Comparisons of the amplitude size and the reproducibility of three different electrodes to record the corneal flash electroretinogram in rodents. Doc. Ophthalmol. 98, 233– 246 (2000).
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.).
About this article
Lineage tracing analysis of cone photoreceptor associated cis-regulatory elements in the developing chicken retina
Scientific Reports (2019)
Frontiers in Endocrinology (2019)
Transcriptional profiling of murine retinas undergoing semi-synchronous cone photoreceptor differentiation
Developmental Biology (2019)
Proceedings of the National Academy of Sciences (2019)