The Thyroid Hormone Receptor<i>β</i>Gene: Structure and Functions in the Brain and Sensory Systems

Jones, Iwan; Srinivas, Maya; Ng, Lily; Forrest, Douglas

doi:10.1089/105072503770867228

Cited by 75 publications

(43 citation statements)

References 145 publications

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“…Thyroid hormone receptors turnover rapidly, so sustained protein levels are not expected (Dace et al, 2000). Whether plasticity in S opsin repression lingers in the late embryonic and early postnatal period remains an Flamant and Samarut (2003) and Jones et al (2003) and targeted TR␤ mutations. Alternate splicing generates TR␤1 and TR␤2, which share exons 3-8 that encode the DNA binding domain, DBD, and ligand binding domain, LBD.…”

Section: Discussionmentioning

confidence: 99%

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Transient expression of thyroid hormone nuclear receptor TRβ2 sets S opsin patterning during cone photoreceptor genesis

Applebury

Farhangfar

Glösmann

et al. 2007

Developmental Dynamics

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Cone photoreceptors in the murine retina are patterned by dorsal repression and ventral activation of S opsin. TR␤2, the nuclear thyroid hormone receptor ␤ isoform 2, regulates dorsal repression. To determine the molecular mechanism by which TR␤2 acts, we compared the spatiotemporal expression of TR␤2 and S opsin from embryonic day (E) 13 through adulthood in C57BL/6 retinae. TR␤2 and S opsin are expressed in cone photoreceptors only. Both are transcribed by E13, and their levels increase with cone genesis. TR␤2 is expressed uniformly, but transiently, across the retina. mRNA levels are maximal by E17 at completion of cone genesis and again minimal before P5. S opsin is also transcribed by E13, but only in ventral cones. Repression in dorsal cones is established by E17, consistent with the occurrence of patterning during cone cell genesis. The uniform expression of TR␤2 suggests that repression of S opsin requires other dorsalspecific factors in addition to TR␤2. The mechanism by which TR␤2 functions was probed in transgenic animals with TR␤2 ablated, TR␤2 that is DNA binding defective, and TR␤2 that is ligand binding defective. These studies show that TR␤2 is necessary for dorsal repression, but not ventral activation of S opsin. TR␤2 must bind DNA and the ligand T3 (thyroid hormone) to repress S opsin. Once repression is established, T3 no longer regulates dorsal S opsin repression in adult animals. The transient, embryonic action of TR␤2 is consistent with a role (direct and/or indirect) in chromatin remodeling that leads to permanent gene silencing in terminally differentiated, dorsal cone photoreceptors.

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Section: Discussionmentioning

confidence: 99%

“…The TR␤1 and TR␤2 isoforms are generated by alternate splicing of a common TR␤ gene. They differ in their N termini, but share the same DNA binding and ligand binding domains (Flamant and Samarut, 2003;Jones et al, 2003;Fig. 5).…”

Section: Dna Binding and T3 Ligand Binding Are Required For Tr␤2 To Amentioning

confidence: 99%

Transient expression of thyroid hormone nuclear receptor TRβ2 sets S opsin patterning during cone photoreceptor genesis

Applebury

Farhangfar

Glösmann

et al. 2007

Developmental Dynamics

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“…Conversely, TRb isoforms are expressed more postnatally within specific neuronal populations such as hippocampal pyramidal and granule cells, paraventricular hypothalamic neurons, and cerebellar Purkinje cells (Bradley et al 1989, Horn & Heuer 2010. Studies in TRb KO mice have shown that these isoforms are predominant in mediating thyroid hormone effects on the development of the vision and auditory systems (Jones et al 2003).…”

Section: Tr Genes and Activitymentioning

confidence: 99%

Thyroid hormones and fetal neurological development

Patel¹,

Landers²,

Li³

et al. 2011

Journal of Endocrinology

187

128

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The development of fetal thyroid function is dependent on the embryogenesis, differentiation, and maturation of the thyroid gland. This is coupled with evolution of the hypothalamic-pituitary-thyroid axis and thyroid hormone metabolism, resulting in the regulation of thyroid hormone action, production, and secretion. Throughout gestation there is a steady supply of maternal thyroxine (T 4 ) which has been observed in embryonic circulation as early as 4 weeks post-implantation. This is essential for normal early fetal neurogenesis. Triiodothyronine concentrations remain very low during gestation due to metabolism via placental and fetal deiodinase type 3. T 4 concentrations are highly regulated to maintain low concentrations, essential for protecting the fetus and reaching key neurological sites such as the cerebral cortex at specific developmental stages. There are many known cell membrane thyroid hormone transporters in fetal brain that play an essential role in regulating thyroid hormone concentrations in key structures. They also provide the route for intracellular thyroid hormone interaction with associated thyroid hormone receptors, which activate their action. There is a growing body of experimental evidence from rats and humans to suggest that even mild maternal hypothyroxinemia may lead to abnormalities in fetal neurological development. Our review will focus on the ontogeny of thyroid hormone in fetal development, with a focus on cell membrane transporters and TR action in the brain.

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“…This explains why no mutations have been identified in CpGs located in regions of the TRβ molecule involved in homodimerization [50]. Dominant negative effect can also manifest through altered association of a mut TRβ with a cofactor, including increased affinity to or decreased release of a corepressor [42,51], or reduced association with a coactivator [40]. In contrast, mut TRβs with complete inability to bind T 3 can paradoxically produce minimal dysfunction if association to corepressor is also reduced [41].…”

Section: Variants Above)mentioning

confidence: 99%