An intron control region differentially regulates expression of thyroid hormone receptor β2 in the cochlea, pituitary, and cone photoreceptors

The Thrb gene, encoding thyroid hormone receptor β (TRβ), serves key roles in endocrine regulation and the development of the senses of hearing and color vision. The versatile functions of this gene depend upon its expression of distinct receptor isoforms by differential promoter activation. The TRβ2 isoform has a particularly specialized distribution including in the anterior pituitary and cochlea. TRβ2 is also found in immature cone photoreceptors where it has a unique role in programming the expression pattern of opsin photopigments that mediate color vision. Given the importance of precise, tissue-specific expression for the function of TRβ2, we investigated the genomic control elements that direct this expression in vivo using lacZ reporter transgenes in mice. The TRβ2 promoter region is sufficient for cochlear expression, whereas a complex intron control region is necessary for pituitary and retinal expression. In the retina, the intron region directs peak expression in the embryo in postmitotic, immature cones. The retinal control region is further subdivided into domains that specify and amplify expression, respectively, indicating that timely, conespecific expression reflects an integrated response to complex signals. The mammalian Thrb gene has therefore incorporated several mechanisms into a multifunctional intron control region that regulates developmental induction of the distant promoter. This specialized genomic organization underlies the unique expression pattern and functions of TRβ2.