NeuroD1 regulates expression of thyroid hormone receptor β2 and cone opsins in the developing mouse retina

The correct patterning of opsin expression in cone photoreceptors is critical for normal color vision. Thyroid hormone, and one of its receptors [thyroid hormone receptor β2 (TRβ2)], is an important regulator of opsin expression during cone photoreceptor development. Mice have two genes, encoding medium-wavelength (M) and short-wavelength (S) cone opsins. Targeted deletion of TRβ2 leads to a uniform expression of S-opsin in all cone photoreceptors and a loss of M-opsin. The control of expression of TRβ2 is therefore central to cone differentiation, yet there is little known about its regulation in the retina. We now report that the proneural bHLH (basic helix-loop-helix) transcription factor, NeuroD1, is necessary for sustained expression of TRβ2 in immature cone photoreceptors. Mice deficient in NeuroD1 develop an opsin phenotype virtually identical with that of TRβ2-deficient mice: all cones express S-opsin, and none expresses M-opsin. The introduction of NeuroD1 into embryonic retinal explants from NeuroD1 ^-/- mice restores TRβ2 expression. NeuroD1 binds an E-box in the intron control region of the TRβ2 gene that mediates cone-specific expression, suggesting that NeuroD1 is a critical contributory factor to the expression of TRβ2 in cones. These results thus connect the proneural pathway with opsin selection to ensure correct cone patterning during retinal development.