Faculty Opinions recommendation of Type 3 deiodinase is critical for the maturation and function of the thyroid axis.

Abstract The role of thyroid hormones (THs) in the central regulation of energy balance is increasingly appreciated. Mice lacking the type 3 deiodinase (DIO3), which inactivates TH, have decreased circulating TH levels relative to control mice as a result of defects in the hypothalamic-pituitary-thyroid axis. However, we have shown that the TH status of the adult Dio3−/− brain is opposite that of the serum, exhibiting enhanced levels of TH action. Because the brain, particularly the hypothalamus, harbors important circuitries that regulate metabolism, we aimed to examine the energy balance phenotype of Dio3−/− mice and determine whether it is associated with hypothalamic abnormalities. Here we show that Dio3−/− mice of both sexes exhibit decreased adiposity, reduced brown and white adipocyte size, and enhanced fat loss in response to triiodothyronine (T3) treatment. They also exhibit increased TH action in the hypothalamus, with abnormal expression and T3 sensitivity of genes integral to the leptin-melanocortin system, including Agrp, Npy, Pomc, and Mc4r. The normal to elevated serum levels of leptin, and elevated and repressed expression of Agrp and Pomc, respectively, suggest a profile of leptin resistance. Interestingly, Dio3−/− mice also display elevated locomotor activity and increased energy expenditure. This occurs in association with expanded nighttime activity periods, suggesting a disrupted circadian rhythm. We conclude that DIO3-mediated regulation of TH action in the central nervous system influences multiple critical determinants of energy balance. Those influences may partially compensate each other, with the result likely contributing to the decreased adiposity observed in Dio3−/− mice.

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Alterations of the thyroid structure and function in experimental hypopinealism

Problems of Endocrinology ◽

10.14341/probl201157232-35 ◽

2011 ◽

Vol 57 (2) ◽

pp. 32-35

Author(s):

L A Bondarenko ◽

L Iu Sergienko ◽

N N Sotnik ◽

A N Cherevko

Keyword(s):

Thyroid Gland ◽

Structural Changes ◽

Structure And Function ◽

Initial Increase ◽

Histological Structure ◽

Pituitary Thyroid Axis ◽

Thyroid Axis ◽

And Function ◽

Sexually Mature

The pituitary-thyroid axis of young sexually mature rabbits kept under a 24-hour daylight photoperiod was shown to undergo phase-modulated variations of hormonal activity with its initial increase (during the first month) and subsequent progressive decrease (within 2-5 months after the onset of exposure to light). These changes correlated with the time-dependent fall in the blood T3, T4, and TSH levels. Simultaneously, the animals developed pathological changes in the histological structure of the thyroid gland similar to those in patients with secondary or tertiary hypothyroidism. It is concluded that hormonal and structural changes in the thyroid gland during long-term hypopinealism should be regarded as an experimental model of hypothyroidism of neuroendocrine origin.

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Type 3 Deiodinase Deficiency Results in Functional Abnormalities at Multiple Levels of the Thyroid Axis

Endocrinology ◽

10.1210/en.2007-0652 ◽

2007 ◽

Vol 148 (12) ◽

pp. 5680-5687 ◽

Cited By ~ 63

Author(s):

Arturo Hernandez ◽

M. Elena Martinez ◽

Xiao-Hui Liao ◽

Jacqueline Van Sande ◽

Samuel Refetoff ◽

...

Keyword(s):

Wild Type ◽

Central Hypothyroidism ◽

Trh Stimulation ◽

Serum T3 ◽

Antithyroid Treatment ◽

Pituitary Glands ◽

Thyroid Axis ◽

Type 3 ◽

Serum Tsh ◽

Hormonal Levels

The type 3 deiodinase (D3) is a selenoenzyme that inactivates thyroid hormones and is highly expressed during development and in the adult central nervous system. We have recently observed that mice lacking D3 activity (D3KO mice) develop perinatal thyrotoxicosis followed in adulthood by a pattern of hormonal levels that is suggestive of central hypothyroidism. In this report we describe the results of additional studies designed to investigate the regulation of the thyroid axis in this unique animal model. Our results demonstrate that the thyroid and pituitary glands of D3KO mice do not respond appropriately to TSH and TRH stimulation, respectively. Furthermore, after induction of severe hypothyroidism by antithyroid treatment, the rise in serum TSH in D3KO mice is only 15% of that observed in wild-type mice. In addition, D3KO animals rendered severely hypothyroid fail to show the expected increase in prepro-TRH mRNA in the paraventricular nucleus of the hypothalamus. Finally, treatment with T3 results in a serum T3 level in D3KO mice that is much higher than that in wild-type mice. This is accompanied by significant weight loss and lethality in mutant animals. In conclusion, the absence of D3 activity results in impaired clearance of T3 and significant defects in the mechanisms regulating the thyroid axis at all levels: hypothalamus, pituitary, and thyroid.

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TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone

The Journal of Cell Biology ◽

10.1083/jcb.201411087 ◽

2015 ◽

Vol 209 (1) ◽

pp. 129-142 ◽

Cited By ~ 59

Author(s):

Elle C. Roberson ◽

William E. Dowdle ◽

Aysegul Ozanturk ◽

Francesc R. Garcia-Gonzalo ◽

Chunmei Li ◽

...

Keyword(s):

Transition Zone ◽

Transmembrane Protein ◽

Syndrome Type ◽

Zone Formation ◽

Meckel Syndrome ◽

Evolutionarily Conserved ◽

Complex Functions ◽

And Function ◽

Type 3

The Meckel syndrome (MKS) complex functions at the transition zone, located between the basal body and axoneme, to regulate the localization of ciliary membrane proteins. We investigated the role of Tmem231, a two-pass transmembrane protein, in MKS complex formation and function. Consistent with a role in transition zone function, mutation of mouse Tmem231 disrupts the localization of proteins including Arl13b and Inpp5e to cilia, resulting in phenotypes characteristic of MKS such as polydactyly and kidney cysts. Tmem231 and B9d1 are essential for each other and other complex components such as Mks1 to localize to the transition zone. As in mouse, the Caenorhabditis elegans orthologue of Tmem231 localizes to and controls transition zone formation and function, suggesting an evolutionarily conserved role for Tmem231. We identified TMEM231 mutations in orofaciodigital syndrome type 3 (OFD3) and MKS patients that compromise transition zone function. Thus, Tmem231 is critical for organizing the MKS complex and controlling ciliary composition, defects in which cause OFD3 and MKS.

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von Willebrand factor propeptide: biology and clinical utility

Blood ◽

10.1182/blood-2015-04-512731 ◽

2015 ◽

Vol 126 (15) ◽

pp. 1753-1761 ◽

Cited By ~ 29

Author(s):

Sandra L. Haberichter

Keyword(s):

Von Willebrand Factor ◽

Clinical Utility ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

True Type ◽

And Function ◽

Type 3 ◽

Von Willebrand ◽

Willebrand Factor ◽

Von Willebrand Factor Propeptide

Abstract von Willebrand factor (VWF) is a large multimeric glycoprotein that mediates the attachment of platelets to damaged endothelium and also serves as the carrier protein for coagulation factor VIII (FVIII), protecting it from proteolytic degradation. Quantitative or qualitative defects in VWF result in von Willebrand disease (VWD), a common inherited bleeding disorder. VWF is synthesized with a very large propeptide (VWFpp) that is critical for intracellular processing of VWF. VWFpp actively participates in the process of VWF multimerization and is essential for trafficking of VWF to the regulated storage pathway. Mutations identified within VWFpp in VWD patients are associated with altered VWF structure and function. The assay of plasma VWFpp has clinical utility in assessing acute and chronic vascular perturbation associated with diseases such as thrombotic thrombocytopenic purpura, sepsis, and diabetes among others. VWFpp assay also has clear utility in the diagnosis of VWD subtypes, particularly in discriminating true type 3 subjects from type 1C (reduced plasma survival of VWF), which is clinically important and has implications for therapeutic treatment.

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Altered retinal structure and function in Spinocerebellar ataxia type 3

10.1101/2022.01.10.475670 ◽

2022 ◽

Author(s):

Vasileios Toulis ◽

Ricardo Casaroli-Marano ◽

Anna Camos-Carreras ◽

Marc Figueras-Roca ◽

Bernardo Sanchez-Dalmau ◽

...

Keyword(s):

Transgenic Mice ◽

Spinocerebellar Ataxia ◽

Neurodegenerative Disorder ◽

Retinal Pigment ◽

Structure And Function ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Retinal Structure ◽

And Function ◽

Type 3

Spinocerebellar ataxia type 3 is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine (polyQ)-encoding CAG repeat in the ATXN3 gene. Because the ATXN3 protein regulates photoreceptor ciliogenesis and phagocytosis, we aimed to explore whether expanded polyQ ATXN3 impacts retinal function and integrity in SCA3 patients and transgenic mice. We evaluated the retinal structure and function in five patients with Spinocerebellar ataxia type 3 and in a transgenic mouse model of this disease (YACMJD84.2, Q84) using, respectively, optical coherence tomography (OCT) and electroretinogram (ERG). We further determined in the transgenic mice: a) the retinal expression pattern of ATXN3 and assessed the distribution of cones and rods by immunofluorescence (IF); and b) the retinal ultrastructure by transmission electron microscopy (TEM). Some patients with Spinocerebellar ataxia type 3 in our cohort revealed: i) reduced central macular thickness indirectly correlated with disease duration; ii) decreased thickness of the macula and the ganglion cell layer, and reduced macula volume inversely correlated with disease severity (SARA score); and iii) electrophysiological dysfunction of cones, rods, and inner retinal cells. Transgenic mice replicated the human OCT and ERG findings with aged homozygous Q84/Q84 mice showing a stronger phenotype accompanied by further thinning of the outer nuclear layer and photoreceptor layer and highly reduced cone and rod activities, thus supporting severe retinal dysfunction in these mice. In addition, Q84 mice showed progressive accumulation of ATXN3-positive aggregates throughout several retinal layers and depletion of cones alongside the disease course. TEM analysis of aged Q84/Q84 mouse retinas supported the IF ATXN3 aggregation findings by revealing the presence of high number of negative electron dense puncta in ganglion cells, inner plexiform and inner nuclear layers, and further showed thinning of the outer plexiform layer, thickening of the retinal pigment epithelium and elongation of apical microvilli. Our results indicate that retinal alterations detected by non-invasive eye examination using OCT and ERG could represent a biological marker of disease progression and severity in patients with Spinocerebellar ataxia type 3.

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Critical Role of Types 2 and 3 Deiodinases in the Negative Regulation of Gene Expression by T3 in the Mouse Cerebral Cortex

Endocrinology ◽

10.1210/en.2011-1905 ◽

2012 ◽

Vol 153 (6) ◽

pp. 2919-2928 ◽

Cited By ~ 47

Author(s):

Arturo Hernandez ◽

Beatriz Morte ◽

Mónica M. Belinchón ◽

Ainhoa Ceballos ◽

Juan Bernal

Keyword(s):

Gene Expression ◽

Cerebral Cortex ◽

Thyroid Hormone ◽

Critical Role ◽

Regulation Of Gene Expression ◽

Control Of Gene Expression ◽

High Doses ◽

And Function ◽

Type 3

Thyroid hormones regulate brain development and function through the control of gene expression, mediated by binding of T3 to nuclear receptors. Brain T3 concentration is tightly controlled by homeostatic mechanisms regulating transport and metabolism of T4 and T3. We have examined the role of the inactivating enzyme type 3 deiodinase (D3) in the regulation of 43 thyroid hormone-dependent genes in the cerebral cortex of 30-d-old mice. D3 inactivation increased slightly the expression of two of 22 positively regulated genes and significantly decreased the expression of seven of 21 negatively regulated genes. Administration of high doses of T3 led to significant changes in the expression of 12 positive genes and three negative genes in wild-type mice. The response to T3 treatment was enhanced in D3-deficient mice, both in the number of genes and in the amplitude of the response, demonstrating the role of D3 in modulating T3 action. Comparison of the effects on gene expression observed in D3 deficiency with those in hypothyroidism, hyperthyroidism, and type 2 deiodinase (D2) deficiency revealed that the negative genes are more sensitive to D2 and D3 deficiencies than the positive genes. This observation indicates that, in normal physiological conditions, D2 and D3 play critical roles in maintaining local T3 concentrations within a very narrow range. It also suggests that negatively and positively regulated genes do not have the same physiological significance or that their regulation by thyroid hormone obeys different paradigms at the molecular or cellular levels.

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Failed Dermal Allograft Procedures in Irreparable Rotator Cuff Tears Can Still Improve Pain and Function. The “Biologic Tuberoplasty Effect”

Orthopaedic Journal of Sports Medicine ◽

10.1177/2325967118s00099 ◽

2018 ◽

Vol 6 (7_suppl4) ◽

pp. 2325967118S0009

Author(s):

Raffy Mirzayan ◽

Michael Allan Stone ◽

Michael Batech ◽

Daniel Acevedo ◽

Anshu Singh

Keyword(s):

Rotator Cuff ◽

Average Length ◽

Rotator Cuff Tears ◽

Double Row ◽

Significant Difference ◽

Goutallier Classification ◽

And Function ◽

Type 3

Objectives: Massive rotator cuff tears (MRCT) are a challenging problem. Dermal allografts have been used in “bridging” procedures and superior capsule reconstruction (SCR). Both have led to clinical improvement, but without correlation with post-operative imaging. The purpose of this study is to examine graft integrity on MRI in patients who underwent an SCR or bridging procedure to determine if graft integrity correlates with functional outcome. We also propose a new classification of dermal allograft re-tear on MRI. Methods: This study was approved by our IRB. Between 2006 and 2016, 11 patients (12 shoulders) underwent a bridging procedure and 10 patients underwent an SCR for MRCT with a dermal allograft by a single surgeon. The grafts were secured to the tuberosity in a double-row, trans-osseous equivalent (DR-TOE) fashion. Pre- and post-operative VAS, acromiohumeral distance (AHD), and ASES scores, and pre-operative Hamada grade and Goutallier classification were prospectively collected and retrospectively reviewed. An MRI was obtained on all patients post-operatively to assess graft integrity. The status of the graft was divided into three types based on MRI findings: Type 1- Graft intact medially (rim of cuff or glenoid) AND laterally (greater tuberosity); Type 2- Graft intact laterally but torn medially; Type 3- Graft torn laterally. The shoulders were then grouped based on these types for further analysis. Results: The average age was 61 (range: 49-73). Average follow-up was 21.6 months (range: 8-80). Average length from surgery to MRI was 13.9 months (range: 6-80). There was a significant improvement in VAS (pre-8.1 to post-1.3) and ASES (pre-26.3 to post-84.6) in Type 1 (P<0.01) and in VAS (pre-7.0 to post-0.7) and ASES (pre-32.6 to post-91.2) in Type 2 (P<0.01). There was no difference in post-operative VAS (1.3 vs 0.7) and ASES (84.6 vs 91.2) between Type 1 and Type 2 (P=0.8). There was no improvement in VAS (pre-7.3 vs post-5.7) and ASES (pre-30.6 vs post-37.2) in Type 3. There was a significant difference in post-operative VAS (5.7 vs 1) and ASES (37.2 vs 88.1) between Type 3 versus Types 1+2, respectively (P<0.01). The AHD decreased in type 3 (pre-7.8 mm to post-3.2 mm, P=0.02) but did not change in Types 1+2 (pre-7.8 mm to post-8.0 mm, P=0.7). Conclusion: In patients who have SCR or “bridging” procedures for MRCT with a dermal allograft, there is significant improvement in VAS and ASES scores if the graft heals to the tuberosity, regardless if it is still intact to the glenoid (in SCR) or the rim of rotator cuff tendon (“bridging”). Individuals whose graft is torn from the tuberosity did not have improvement in VAS or ASES scores versus baseline. There was no significant difference in AHD in all groups. We believe that the dermal graft acts as a “biologic (interpositional) tuberoplasty,” preventing bone-to-bone contact between the tuberosity and the acromion, thus eliminating pain and improving function. We still recommend performing an SCR when indicated because it has been shown to restore the normal kinematics of the shoulder in a laboratory setting. However, careful attention should be paid to the repair of the graft to the tuberosity, so that in case the primary procedure fails medially, the graft can still improve pain and function.

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Gene Expression from the Imprinted Dio3 Locus Is Associated with Cell Proliferation of Cultured Brown Adipocytes

Endocrinology ◽

10.1210/en.2007-0029 ◽

2007 ◽

Vol 148 (8) ◽

pp. 3968-3976 ◽

Cited By ~ 33

Author(s):

Arturo Hernandez ◽

Bibian Garcia ◽

Maria-Jesus Obregon

Keyword(s):

Gene Expression ◽

Thyroid Hormones ◽

Precursor Cells ◽

Proliferating Cells ◽

Antisense Gene ◽

Brown Adipocytes ◽

Brown Adipose ◽

Proliferation And Differentiation ◽

And Function ◽

Type 3

Active thyroid hormones are critical for the differentiation and function of brown adipose tissue. However, we have observed high basal and induced levels of type 3 deiodinase (D3), an enzyme that inactivates thyroid hormones and is coded by the imprinted gene Dio3, in differentiating brown preadipocytes in primary culture. We find that D3 activity and mRNA expression strongly correlate with the rate of proliferation of undifferentiated precursor cells under various conditions. Furthermore, differentiation of precursor cells to adipocytes is associated with decreased levels of D3 expression, and only very low levels of D3 mRNA are found in mature adipocytes. Dlk1, an inhibitor of adipocyte differentiation and a paternally expressed gene located in the same imprinted domain as Dio3, displayed changes in expression that parallel those of Dio3. In contrast, a 4-kb transcript for Dio3os, an antisense gene also located in the same imprinted domain, is markedly up-regulated in differentiated adipocytes. We conclude that D3 expression in differentiating preadipocytes is primarily linked to proliferating cells, whereas Dio3os expression is associated with mature adipocytes. Our results suggest that genomic imprinting and gene expression at the Dlk1/Dio3 imprinted domain may play a role in the regulation of adipocyte proliferation and differentiation.

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