TOPIC: Patterning of retinal cone photoreceptor development
Title: NeuroD1 regulates expression of thyroid hormone receptor '2 and cone opsins in the developing mouse retina.
Authors: Liu H, Etter P, Hayes S, Jones I, Nelson B, Hartman B, Forrest D, & Reh T.
Reference: The Journal of Neuroscience, 28: 749-756, 2008
The correct patterning of opsin expression in cone photoreceptors is critical for normal color vision. Thyroid hormone and one of its receptors (TR'2) are important regulators of opsin expression during cone photoreceptor development. Mice have two genes, encoding medium-wavelength (M) and short-wavelength (S) cone opsins. Targeted deletion of TR'2 leads to a uniform expression of S-opsin in all cone photoreceptors and the loss of M-opsin. The control of expression of TR'2 is therefore central to cone differentiation, yet there is little known about its regulation in the retina. Several transcription factors are known to be expressed in developing cones before the onset of TR'2, including those belonging to the basic helix-loop-helix (bHLH) class. Recent analysis of the TR' gene identified cone-specific, intronic control regions containing than E-box consensus site for bHLH.
To determine whether the bHLH transcription factor, NeuroD1, is necessary for sustained expression of TR'2 in immature cone photoreceptors.
Mice deficient in NeuroD1 madonna pokies were used to assess the role of this transcription factor in the expression of TR'2 and the resulting effect on opsins during cone photoreceptor development.
Mice deficient in NeuroD1 develop an opsin phenotype virtually identical with that of TR'2-deficient mice: all cones express S-opsin, and none expresses M-opsin. The introduction of NeuroD1 into embryonic retinal explants from NeuroD1 -/- mice restores TR'2 expression. NeuroD1 binds an E-box in the intron control region of the TR'2 gene that mediates cone-specific expression, suggesting that NeuroD1 is a critical contributory factor to the expression of TR'2 in cones.
These results thus connect the proneural pathway with opsin selection to ensure correct cone patterning during retinal development.
This work provides a mechanism for the local expression of the specific TR'2 isoform. However, although NeuroD1 is required for TR'2 expression in the retinal cones, it cannot do so in non permissive cell types in transfection assays. This suggests that the induction process requires the cooperation with other cell-specific factors. The full unravelling of the mechanism regulating cone specific TR'2 gene expression will require the identification of new genes involved in correct cone patterning during retinal development.
Summary and commentary prepared by Samuel Refetoff (Related to Chapter 3d of TDM)