Type 3 Deiodinase, a Thyroid-Hormone Inactivating Enzyme, Regulates Maturation and Survival of Cone Photoreceptors

Abstract

Purpose: : To investigate the role of Type 3 deiodinase (D3) in the development of the mouse retina.

Methods: : We studied retinal function in (1) mice that have D3, a thyroid hormone-inactivating enzyme encoded by Dio3, inactivated by deletion of the Dio3 gene (Dio3-/-); (2) mice with both the D3 and thyroid hormone receptor, TRβ2 deleted (Dio3-/- Thrb2-/-).

Results: : In Dio3-/- animals, cones are formed, but ~80% of both M and S sub-types are lost through increased rates of neonatal cell death, though rod photoreceptors remain morphologically intact. ERG studies on these animals revealed a drastic reduction in amplitude of the cone b-wave from 223±57 µV in wild type (WT) to 45±7 µV in Dio3-/- mice. These results are consistent with ~80% cone loss observed in morphological studies. Rod-driven ERG components, both the a- and b-wave, were only moderately (by ~25%) though statistically significantly diminished in the Dio3-/- animals. Elimination of a thyroid hormone receptor, TRβ2, in addition to D3 in Dio3-/- Thrb2-/- mice resulted in rescue of cones. The amplitude of the saturating cone b-wave in these animals was similar to that in the WT mice. The spectral sensitivity of cone ERG in the Dio3-/- Thrb2-/- was characterized with enhanced sensitivity to the near UV (365 nm) light and dramatic decrease in sensitivity to illumination in the M pigment band, similar to Thrb2-/- mice. The Dio3-/- Thrb2-/- mice also exhibited a ~25% lower amplitudes of the saturating rod a-wave.

Conclusions: : D3, a thyroid-hormone inactivating enzyme, regulates maturation and survival of cone photoreceptors. In absence of the D3 80% of cones die within two days of birth. The cone loss in Dio3-/- mice is reversed upon deletion of TRβ2 receptor for the hormone; the overwhelming majority of cones then acquires a pure S opsin identity. Thus, decisions in cone development are balanced by thyroid hormone: D3 normally limits the level of hormonal stimulation to permit opsin patterning whereas excessive stimulation in Dio3-/- mice selectively eliminates cones.

Keywords: electroretinography: non-clinical • photoreceptors • development