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The thyroid hormone clearing type 3 deiodinase protects from cardiac congenital abnormalities

ABSTRACT: The thyroid hormone clearing type 3 deiodinase protects from cardiac congenital abnormalities

PROVIDER: PRJNA815050 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18299808.fastq.gz	Fastqsanger.gz
	SRR18299809.fastq.gz	Fastqsanger.gz
	SRR18299810.fastq.gz	Fastqsanger.gz
	SRR18299811.fastq.gz	Fastqsanger.gz
	SRR18299812.fastq.gz	Fastqsanger.gz

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The thyroid hormone clearing type 3 deiodinase protects from cardiac congenital abnormalities

Project description:We examined the impact of thyroid hormone excess on the mouse fetal heart utilizing a model of deficiency in DIO3, the enzyme that is responsible for clearing thyroid hormones

2022-11-23 | GSE198416 | GEO

The type 3 deiodinase contributes to the reduced sensitivity of the fetal brain to thyroid hormone

Project description:We examined the impact of thyroid hormone on the mouse fetal brain utilizing a model of deficiency in DIO3, the enzyme that is responsible for clearing thyroid hormones

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Thyroid hormone regulated genes in the neonatal testis

Project description:An excess in thyroid hormone during rodent neonatal life causes abnormal prolifration and maturation of testicular cells, leading to reduced testis size and impairments in steroidogenesis, Sertoli cell function, spermatogenesis and fertility. The high expression of type 3 deiodinase in the neonatal testis protects this tissue from premature exposure to thyroid hormones, since this gene (Dio3) function is to degrade thyroid hormones. DIO3-deficient mice (Dio3KO) exhibit a marked reduction in Sertoli cell proliferation and testis size, abnormalities in the reproductive axis and impaired fertility (Martinez et al. 2016, Endocrinology157:1276). To identify genes that are untimely regulated by thyroid hormone in the developing testes, we have performed RNAseq in testis total RNA from wild type and DIO3KO mouse neonates.

2019-08-01 | GSE117157 | GEO

Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-Associated Pulmonary Abnormalities

Project description:Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-Associated Pulmonary Abnormalities

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Genetic Abnormalities in Large to Giant Congenital Nevi: Beyond NRAS mutations

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The thyroid hormone-inactivating deiodinase functions as a homodimer.

Project description:The type 3 deiodinase (D3) inactivates thyroid hormone action by catalyzing tissue-specific inner ring deiodination, predominantly during embryonic development. D3 has gained much attention as a player in the euthyroid sick syndrome, given its robust reactivation during injury and/or illness. Whereas much of the structure biology of the deiodinases is derived from studies with D2, a dimeric endoplasmic reticulum obligatory activating deiodinase, little is known about the holostructure of the plasma membrane resident D3, the deiodinase capable of thyroid hormone inactivation. Here we used fluorescence resonance energy transfer in live cells to demonstrate that D3 exists as homodimer. While D3 homodimerized in its native state, minor heterodimerization was also observed between D3:D1 and D3:D2 in intact cells, the significance of which remains elusive. Incubation with 0.5-1.2 m urea resulted in loss of D3 homodimerization as assessed by bioluminescence resonance energy transfer and a proportional loss of enzyme activity, to a maximum of approximately 50%. Protein modeling using a D2-based scaffold identified potential dimerization surfaces in the transmembrane and globular domains. Truncation of the transmembrane domain (DeltaD3) abrogated dimerization and deiodinase activity except when coexpressed with full-length catalytically inactive deiodinase, thus assembled as DeltaD3:D3 dimer; thus the D3 globular domain also exhibits dimerization surfaces. In conclusion, the inactivating deiodinase D3 exists as homo- or heterodimer in living intact cells, a feature that is critical for their catalytic activities.

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Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton.

Project description:Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To study this, pregnant mice were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved up to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocytes, in addition to a slight delay in endochondral and intramembranous ossification. This suggests that up to E16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly ( approximately 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast, D2 mRNA expression increased significantly by E18.5 and markedly ( approximately 2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development.

| S-EPMC4683160 | biostudies-literature

Cerebellar abnormalities in mice lacking type 3 deiodinase and partial reversal of phenotype by deletion of thyroid hormone receptor α1.

Project description:Thyroid hormone serves many functions throughout brain development, but the mechanisms that control the timing of its actions in specific brain regions are poorly understood. In the cerebellum, thyroid hormone controls formation of the transient external germinal layer, which contains proliferative granule cell precursors, subsequent granule cell migration, and cerebellar foliation. We report that the thyroid hormone-inactivating type 3 deiodinase (encoded by Dio3) is expressed in the mouse cerebellum at embryonic and neonatal stages, suggesting a need to protect cerebellar tissues from premature stimulation by thyroid hormone. Dio3(-/-) mice displayed reduced foliation, accelerated disappearance of the external germinal layer, and premature expansion of the molecular layer at juvenile ages. Furthermore, Dio3(-/-) mice exhibited locomotor behavioral abnormalities and impaired ability in descending a vertical pole. To ascertain that these phenotypes resulted from inappropriate exposure to thyroid hormone, thyroid hormone receptor α1 (TRα1) was removed from Dio3(-/-) mice, which substantially corrected the cerebellar and behavioral phenotypes. Deletion of TRα1 did not correct the previously reported small thyroid gland or deafness in Dio3(-/-) mice, indicating that Dio3 controls the activation of specific receptor isoforms in different tissues. These findings suggest that type 3 deiodinase constrains the timing of thyroid hormone action during cerebellar development.

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Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling.

Project description:The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biologically active molecule T(3) during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-kappaB, growth factors, bile acids, hypoxia-inducible factor-1alpha, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.

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The type 3 deiodinase contributes to the reduced sensitivity of the fetal brain to thyroid hormone

Project description:The type 3 deiodinase contributes to the reduced sensitivity of the fetal brain to thyroid hormone

| PRJNA721678 | ENA