Thyroid hormone receptors: lessons from knockout and knock-in mutant mice

Flamant, Frédéric; Samarut, Jacques

doi:10.1016/s1043-2760(02)00043-7

Cited by 287 publications

(181 citation statements)

References 58 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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“…Two genes (THRa and THRb) have been identified that give rise to several protein isoforms by alternative splicing and promoter usage (Bassett et al, 2003;Flamant and Samarut, 2003). Among these different products only TRalpha1, TRbeta1, TRbeta2 and TRbeta3 can be considered as thyroid hormone receptors as they contain both a T3-and a DNA binding domain whereas the physiological function of the non-receptor proteins that are also encoded by THRa and THRb is still unclear.…”

Section: Role Of Thyroid Hormone Receptorsmentioning

confidence: 99%

“…Despite the widespread distribution of thyroid hormone receptors in the CNS mice deficient in specific receptor isoforms or even in all thyroid hormone receptors do not replicate the strong phenotype of hypothyroid animals indicating that the lack of the ligand T3 has much stronger detrimental consequences than the lack of its receptors (for reviews on the phenotype of thyroid hormone receptor mutant mice see (Forrest and Vennstrom, 2000;O'Shea and Williams, 2002;Flamant and Samarut, 2003;Bernal, 2007). According to the current model that was put forward to explain these discrepancies the structural defects associated with hypothyroidism are primarily caused by unliganded receptors (particularly TRalpha1) that exert aporeceptor activity and thereby repress a program of differentiation.…”

Section: Role Of Thyroid Hormone Receptorsmentioning

confidence: 99%

Thyroid hormone action during brain development: More questions than answers

Horn

Heuer

2010

Molecular and Cellular Endocrinology

165

106

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“…A TRE has been reported in the promoter of UCP1 gene, indicating that thyroid hormone is at least important for UCP1 gene transcription (Branco et al, 1999). TRα1 deficient mice have decreased body temperature, suggesting TRα1 is required to maintain temperature homeostasis (Flamant and Samarut, 2003;Marrif et al, 2005). Using TRβ-specific ligand, GC-1, a differential effect of different TR isoforms was revealed.…”

Section: Regulation Of Adaptive Thermogenesis In Brown Adipose Tissuementioning

confidence: 99%

Thyroid hormone action in metabolic regulation

2011

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Thyroid hormone plays pivotal roles in growth, differentiation, development and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms, diverse thyroid hormone response elements, different heterodimeric partners, coregulators, and the cellular location of TRs. In the present review, we summarize recent advance in understanding the molecular mechanisms of thyroid hormone action obtained from human subject research, thyroid hormone mimetics application, TR isoform-specific knock-in mouse models, and mitochondrion study with highlights in metabolic regulations. Finally, as future perspectives, we share our thoughts about current challenges and possible approaches to promote our knowledge of thyroid hormone action in metabolism.

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Thyroid hormone receptors: lessons from knockout and knock-in mutant mice

Cited by 287 publications

References 58 publications

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

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

Thyroid hormone action during brain development: More questions than answers

Thyroid hormone action in metabolic regulation

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