Structure of the growth hormone-encoding gene and its promoter in mice

Genetic evidence from patients with mutations of the thyroid hormone receptor α gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TRα1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TRα1 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1 PV mice, expressing a dominant negative TRα1 mutant (TRα1PV), with mice expressing a mutant Ncor1 allele (Ncor1 ΔID mice) that cannot recruit the TR or PV mutant. TRα1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1ΔID ameliorated abnormalities in the thyroid-pituitary axis of Thra1 PV/+ mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1 PV/+ mice expressing NCOR1ΔID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor γ and CCAAT/enhancerbinding protein α gene, due to the inability of TRα1PV to recruit NCOR1ΔID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TRα1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TRα1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TRα1 mutant-mediated hypothyroidism in patients.growth retardation | lipid metabolism | fertility defect T he thyroid hormone T3 regulates growth and development and maintains metabolic homeostasis in humans. The genomic signaling by T3 is via the thyroid hormone receptor (TR) isoforms α1, β1, and β2, which are encoded by the THRA and THRB genes located on two different chromosomes. These TR isoforms share extensive sequence homology in the DNA and T3 binding domains but differ in the amino terminal A/B domains (1). TR binds to the thyroid hormone response elements (TREs) and recruits nuclear coregulatory proteins to regulate gene transcription. In the absence of T3, TRs recruit the nuclear corepressors (NCOR1 and NCOR2) for transcriptional repression on the T3 positively regulated genes. In the presence of T3, the T3-bound TR undergoes structural changes, resulting in the release of corepressors, allowing recruitment of nuclear receptor coactivators (e.g., SRC-1) to facilitate transcription activation (2, 3).The critical roles of TR in mediating biological functions of T3 are clearly evident, in that mutations of the THRB gene cause resistance to thyroid hormone (RTH) (3). The intriguing observation that no mutations of the THRA gene were ever found in RTH patients raised the possibilities that mutations of the THRA gene could be embryonic lethal or could confer different clinical manifestations. These possibilities were explored by using a powerful mouse genetic approach. Targeting a ...

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“…S2). Gh is a TR directly regulated gene in which the thyroid hormone response element is well defined (15). Fig.…”

Section: Expression Of Ncor1δid Lessens the Extent Of Retarded Growth Inmentioning

confidence: 99%

Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α

Fozzatti

Kim

Park

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…POMC (ACTH, MSH) No (Drouin et al, 1985) FSH No (Kumar, 1994-direct submission) GH No (Das et al, 1996) LH No (Kaiser et al, 1998) Prolactin No (Gubbins et al, 1980) TSH (beta subunit) Yes (3) (Croyle and Maurer, 1984) …”

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confidence: 99%

The regulation of neuroendocrine function: Timing is everything

Kriegsfeld

Silver

2006

Hormones and Behavior

129

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Hormone secretion is highly organized temporally, achieving optimal biological functioning and health. The master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates the timing of circadian rhythms, including daily control of hormone secretion. In the brain, the SCN drives hormone secretion. In some instances, SCN neurons make direct synaptic connections with neurosecretory neurons. In other instances, SCN signals set the phase of "clock genes" that regulate circadian function at the cellular level within neurosecretory cells. The protein products of these clock genes can also exert direct transcriptional control over neuroendocrine releasing factors. Clock genes and proteins are also expressed in peripheral endocrine organs providing additional modes of temporal control. Finally, the SCN signals endocrine glands via the autonomic nervous system, allowing for rapid regulation via multisynaptic pathways. Thus, the circadian system achieves temporal regulation of endocrine function by a combination of genetic, cellular, and neural regulatory mechanisms to ensure that each response occurs in its correct temporal niche. The availability of tools to assess the phase of molecular/cellular clocks and of powerful tract tracing methods to assess connections between "clock cells" and their targets provides an opportunity to examine circadian-controlled aspects of neurosecretion, in the search for general principles by which the endocrine system is organized. KeywordsCircadian; Diurnal; Endocrinel; Neurosecretion; Clock genes; Suprachiasmatic Circadian aspects of reproductionThe importance of circadian (about a day) timing in hormone production/secretion has been known since the 1950s when Everett and Sawyer determined that a stimulatory signal occurring during a narrow temporal window on the afternoon of proestrus is necessary for induction of ovulation later that night (Everett and Sawyer, 1950). Such close temporal organization is important for successful reproduction, as numerous hormone-dependent behavioral and physiological processes must be coordinated. If optimal temporal relationships are disrupted, pronounced deficits in fertility can result. For example, ovulation, behavioral estrus, fertilization, and pregnancy maintenance require a specific

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“…The structure and organisation of the GH gene in rat and mouse are similar to those of other non-primate GH genes (Barta et al 1981, Das et al 1996, comprising five exons interrupted by four introns. The rat gene differs from that of other mammals, including mouse, in that the second intron includes a repetitive sequence of approximately 500 bp (Barta et al 1981).…”

Section: Introductionmentioning

confidence: 78%

“…Similarly, a putative site for the polyadenylation signal at the 3 UTR of the gene should be present at nucleotides 1652-1657. The transcription start point (tsp) in the mouse and hamster genes is a C residue (Southard et al 1991, Das et al 1996, found at position 82 of the mole rat sequence, whereas the rat tsp (Barta et al 1981) lies one base downstream (an A at base 83 of the present sequence). Mole rat, like mouse, differs from rat in the size of the second intron; the dispersed repetitive sequence, flanked by short direct repeats, that is found in the rat intron 2 (Barta et al 1981, Page et al 1981 is not found in mole rat or mouse.…”

Section: Resultsmentioning

confidence: 99%

Cloning and characterisation of the gene encoding mole rat (Spalax ehrenbergi) growth hormone

Lioupis

Nevo²,

Wallis³

1999

Journal of Molecular Endocrinology

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In mammals the structure of pituitary GH is generally strongly conserved, reflecting a slow basal rate of molecular evolution. However, on a few occasions the rate has increased -markedly during the evolution of primates and artiodactyls, and to a small extent during the evolution of rodents and rabbit -giving rise to marked differences between GH sequences of these species. In order to extend knowledge of rodent GHs we have cloned and characterised part of the GH gene of the Eurasian mole rat (Spalax ehrenbergi) using genomic DNA and a PCR technique. The sequence of all of the coding region and 5 untranslated region (UTR), most of the 3 UTR and part of the promoter region is described. The overall organisation of the mole rat GH gene is similar to that of GH genes from other mammals. The proximal Pit-1 sequence in the gene promoter differs somewhat from that of rat or mouse. The deduced sequence for the mature GH from mole rat differs from that of pig GH (thought to be identical to the ancestral placental mammal GH sequence) at 7 residues and from rat, mouse and hamster GHs at 9 to 12 residues. Only one or two of these substitutions involve residues close to the receptor-binding sites of the hormone.

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Structure of the growth hormone-encoding gene and its promoter in mice

Cited by 34 publications

References 19 publications

Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α

Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α

The regulation of neuroendocrine function: Timing is everything

Cloning and characterisation of the gene encoding mole rat (Spalax ehrenbergi) growth hormone

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