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The nuclear receptors of thyroid hormone exert a broad influence on brain development and then on adult brain physiology. However the cell autonomous function of the receptors is combined with their indirect influence on cellular interactions. Mouse genetics allows to distinguish between these two mode of action. It revealed that one of the main cell-autonomous functions of these receptors is to promote the maturation of GABAergic neurons. This review presents our current understanding of the action of thyroid hormone on this class of neurons, which are the main inhibitory neurons in most brain areas.
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Gestating mice were exposed to three chemicals, tetrabromo-bisphenol A (TBBPA; 2mg/kg/day)), amitrole (25 and 50mg/kg/day) and pyraclostrobin (0.4 and 2mg/kg/day) to assess their capacity to act as thyroid hormone disruptors and compromise neurodevelopment. Propyl-thio-uracyl, a known pharmacological inhibitor of thyroid gland secretion, was used at both high and low dose as a reference thyroid hormone disruptor (1 ppm, 1500 ppm). A combination of plasma metabolomics and striatum transcriptomics revealed the induced change in pups at the postnatal stages. Although the underlying mechanism is unlikely to involve thyroid hormone disruption, these chemicals had a detectable effect on pups' neurodevelopment.
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Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.
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Sordera , Pérdida Auditiva Central , Atrofia Óptica Autosómica Dominante , Animales , Humanos , Ratones , GTP Fosfohidrolasas/genética , Pérdida Auditiva Central/genética , Mutación , Atrofia Óptica Autosómica Dominante/genéticaRESUMEN
Mice were exposed to a low dose of the model thyroid hormone disruptor, propylthiouracil. Although this had only a modest effect on maternal thyroid hormones production, postnatal analysis of the pups' plasma by mass spectrometry and the brain striatum by RNA sequencing gave evidence of low lasting changes that could reflect an adverse effect on neurodevelopment. Overall, these methods proved to be sensitive enough to detect minor disruptions of thyroid hormone signalling in vivo.
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Hormonas Tiroideas , Transcriptoma , Animales , Ratones , Glándula Tiroides , Propiltiouracilo/farmacología , EncéfaloRESUMEN
Thyroid hormone (TH) signaling plays a major role in mammalian brain development. Data obtained in the past years in animal models have pinpointed GABAergic neurons as a major target of TH signaling during development, which opens up new perspectives to further investigate the mechanisms by which TH affects brain development. The aim of the present review is to gather the available information about the involvement of TH in the maturation of GABAergic neurons. After giving an overview of the kinds of neurological disorders that may arise from disruption of TH signaling during brain development in humans, we will take a historical perspective to show how rodent models of hypothyroidism have gradually pointed to GABAergic neurons as a main target of TH signaling during brain development. The third part of this review underscores the challenges that are encountered when conducting gene expression studies to investigate the molecular mechanisms that are at play downstream of TH receptors during brain development. Unravelling the mechanisms of action of TH in the developing brain should help make progress in the prevention and treatment of several neurological disorders, including autism and epilepsy.
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Hipotiroidismo , Enfermedades del Sistema Nervioso , Animales , Humanos , Hormonas Tiroideas/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Hipotiroidismo/genética , Roedores/metabolismo , Mamíferos/metabolismo , Neuronas GABAérgicas/metabolismoRESUMEN
In rats, hypothyroidism during fetal and neonatal development can disrupt neuronal migration and induce the formation of periventricular heterotopia in the brain. However, it remains uncertain if heterotopia also manifest in mice after developmental hypothyroidism and whether they could be used as a toxicological endpoint to detect TH-mediated effects caused by TH system disrupting chemicals. Here, we performed a mouse study where we induced severe hypothyroidism by exposing pregnant mice (n = 3) to a very high dose of propylthiouracil (PTU) (1500 ppm) in the diet. This, to obtain best chances of detecting heterotopia. We found what appears to be very small heterotopia in 4 out of the 8 PTU-exposed pups. Although the incidence rate could suggest some utility for this endpoint, the small size of the ectopic neuronal clusters at maximum hypothyroidism excludes the utility of heterotopia in mouse toxicity studies aimed to detect TH system disrupting chemicals. On the other hand, parvalbumin expression was manifestly lower in the cortex of hypothyroid mouse offspring demonstrating that offspring TH-deficiency caused an effect on the developing brain. Based on overall results, we conclude that heterotopia formation in mice is not a useful toxicological endpoint for examining TH-mediated developmental neurotoxicity.
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Hipotiroidismo , Heterotopia Nodular Periventricular , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Humanos , Animales , Ratas , Ratones , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Exposición Materna , Hormonas Tiroideas/metabolismo , Hipotiroidismo/inducido químicamente , Hipotiroidismo/metabolismo , Propiltiouracilo/toxicidadRESUMEN
Thyroid hormone increases energy expenditure. Its action is mediated by TR, nuclear receptors present in peripheral tissues and in the central nervous system, particularly in hypothalamic neurons. Here, we address the importance of thyroid hormone signaling in neurons, in general for the regulation of energy expenditure. We generated mice devoid of functional TR in neurons using the Cre/LoxP system. In hypothalamus, which is the center for metabolic regulation, mutations were present in 20% to 42% of the neurons. Phenotyping was performed under physiological conditions that trigger adaptive thermogenesis: cold and high-fat diet (HFD) feeding. Mutant mice displayed impaired thermogenic potential in brown and inguinal white adipose tissues and were more prone to diet-induced obesity. They showed a decreased energy expenditure on chow diet and gained more weight on HFD. This higher sensitivity to obesity disappeared at thermoneutrality. Concomitantly, the AMPK pathway was activated in the ventromedial hypothalamus of the mutants as compared with the controls. In agreement, sympathetic nervous system (SNS) output, visualized by tyrosine hydroxylase expression, was lower in the brown adipose tissue of the mutants. In contrast, absence of TR signaling in the mutants did not affect their ability to respond to cold exposure. This study provides the first genetic evidence that thyroid hormone signaling exerts a significant influence in neurons to stimulate energy expenditure in some physiological context of adaptive thermogenesis. TR function in neurons to limit weight gain in response to HFD and this effect is associated with a potentiation of SNS output.
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Obesidad , Hormonas Tiroideas , Masculino , Ratones , Animales , Obesidad/genética , Obesidad/metabolismo , Hormonas Tiroideas/metabolismo , Dieta Alta en Grasa/efectos adversos , Tejido Adiposo Pardo/metabolismo , Neuronas/metabolismo , Termogénesis/fisiología , Metabolismo Energético/genéticaRESUMEN
Thyroid hormones are known to trigger metamorphosis in an amphibian. This review discusses the hypothesis according to which they act in a similar manner to synchronize the post-natal development of mice, using brain, brown adipose tissue, and heart as examples.
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Receptores de Hormona Tiroidea , Hormonas Tiroideas , Animales , Ratones , Metamorfosis Biológica , AnfibiosRESUMEN
Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3 signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT.
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Adipocitos Marrones , Termogénesis , Ratones , Masculino , Animales , Adipocitos Marrones/metabolismo , Termogénesis/fisiología , Tejido Adiposo Pardo/metabolismo , Hormonas Tiroideas/metabolismo , Metabolismo Energético , Ratones Transgénicos , Ratones Endogámicos C57BLRESUMEN
We gathered available RNA-seq and ChIP-seq data in a single database to better characterize the target genes of thyroid hormone receptors in several cell types. This database can serve as a resource to analyze the mode of action of thyroid hormone (T3). Additionally, it is an easy-to-use and convenient tool to obtain information on specific genes regarding T3 regulation or to extract large gene lists of interest according to the users' criteria. Overall, this atlas is a unique compilation of recent sequencing data focusing on T3, its receptors, modes of action, targets and roles, which may benefit researchers within the field. A preliminary analysis indicates extensive variations in the repertoire of target genes where transcription is upregulated by chromatin-bound nuclear receptors. Although it has a major influence, chromatin accessibility is not the only parameter that determines the cellular selectivity of the hormonal response.
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Receptores de Hormona Tiroidea , Hormonas Tiroideas , Animales , Cromatina/genética , Ratones , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/genética , Hormonas Tiroideas/metabolismo , Triyodotironina/metabolismoRESUMEN
Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.
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Transportadores de Ácidos Monocarboxílicos , Simportadores , Animales , Ratones , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/genética , Simportadores/metabolismo , Sistemas CRISPR-Cas , Hormonas Tiroideas/metabolismo , Modelos Animales de Enfermedad , Mamíferos/metabolismoRESUMEN
When bound to thyroid hormone, the nuclear receptor TRα1 activates the transcription of a number of genes in many cell types. It mainly acts by binding DNA as a heterodimer with retinoid X receptors at specific response elements related to the DR4 consensus sequence. However, the number of DR4-like elements in the genome exceed by far the number of occupied sites, indicating that minor variations in nucleotides composition deeply influence the DNA-binding capacity and transactivation activity of TRα1. An improved protocol of synthetic self-transcribing active regulatory region sequencing was used to quantitatively assess the transcriptional activity of thousands of synthetic sites in parallel. This functional screen highlights a strong correlation between the affinity of the heterodimers for DNA and their capacity to mediate the thyroid hormone response.
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Receptores de Ácido Retinoico , Receptores de Hormona Tiroidea , ADN/metabolismo , Receptores de Ácido Retinoico/genética , Receptores de Hormona Tiroidea/metabolismo , Elementos de Respuesta , Receptores X Retinoide/genética , Hormonas TiroideasRESUMEN
Resistance to thyroid hormone due to mutations in THRA, which encodes the thyroid hormone receptor α (TRα1), shows variable clinical presentation. Mutations affecting TRß1 and TRß2 cause deafness in mice and have been associated with deafness in humans. To test whether TRα1 also affects hearing function, we used mice heterozygous for a frameshift mutation in Thra that is similar to human THRA mutations (ThraS1/+ mice) and reduces tissue sensitivity to thyroid hormone. Compared to wild-type littermates, ThraS1/+ mice showed moderate high-frequency sensorineural hearing loss as juveniles and increased age-related hearing loss. Ultrastructural examination revealed aberrant orientation of ~20% of sensory outer hair cells (OHCs), as well as increased numbers of mitochondria with fragmented morphology and autophagic vacuoles in both OHCs and auditory nerve fibers. Molecular dissection of the OHC lateral wall components revealed that the potassium ion channel Kcnq4 was aberrantly targeted to the cytoplasm of mutant OHCs. In addition, mutant cochleae showed increased oxidative stress, autophagy, and mitophagy associated with greater age-related cochlear cell damage, demonstrating that TRα1 is required for proper development of OHCs and for maintenance of OHC function. These findings suggest that patients with THRA mutations may present underdiagnosed, mild hearing loss and may be more susceptible to age-related hearing loss.
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Sordera , Pérdida Auditiva , Receptores alfa de Hormona Tiroidea , Animales , Pérdida Auditiva/genética , Ratones , Mutación , Receptores alfa de Hormona Tiroidea/genética , Hormonas TiroideasRESUMEN
Nanopesticides are innovative pesticides involving engineered nanomaterials in their formulation to increase the efficiency of plant protection products, while mitigating their environmental impact. Despite the predicted growth of the nanopesticide use, no data is available on their inhalation toxicity and the potential cocktail effects between their components. In particular, the neurodevelopmental toxicity caused by prenatal exposures might have long lasting consequences. In the present study, we repeatedly exposed gestating mice in a whole-body exposure chamber to three aerosols, involving the paraquat herbicide, nanoscaled titanium dioxide particles (nTiO2), or a mixture of both. Particle number concentrations and total mass concentrations were followed to enable a metrological follow-up of the exposure sessions. Based on the aerosols characteristics, the alveolar deposited dose in mice was then estimated. RNA-seq was used to highlight dysregulations in the striatum of pups in response to the in utero exposure. Modifications in gene expression were identified at post-natal day 14, which might reflect neurodevelopmental alterations in this key brain area. The data suggest an alteration in the mitochondrial function following paraquat exposure, which is reminiscent of the pathological process leading to Parkinson disease. Markers of different cell lineages were dysregulated, showing effects, which were not limited to dopaminergic neurons. Exposure to the nTiO2 aerosol modulated the regulation of cytokines and neurotransmitters pathways, perhaps reflecting a minor neuroinflammation. No synergy was found between paraquat and nTiO2. Instead, the neurodevelopmental effects were surprisingly lower than the one measured for each substance separately.
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Paraquat , Efectos Tardíos de la Exposición Prenatal , Aerosoles , Animales , Encéfalo , Femenino , Expresión Génica , Exposición por Inhalación , Ratones , Paraquat/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/genética , Titanio/toxicidadRESUMEN
[This corrects the article DOI: 10.1016/j.isci.2021.102957.].
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Chemicals acting as thyroid hormone disruptors (THDs) are of a particular concern for public health, considering the importance of this hormone in neurodevelopment and metabolic processes. They might either alter the circulating level of thyroid hormone (TH) or interfere with the cellular response to the hormonal stimulation. In order to assess this later possibility we selected 39 pesticides and combined several in vitro tests. Reporter assays respectively addressed the transactivation capacity of the full-length TH nuclear receptor TRα1, the transactivation capacity of its C-terminal ligand binding domain, or the ability of the hormone to destabilize the interaction between TRα1 and the transcriptional corepressor NcoR. Although some pesticides elicit a cellular response, which sometimes interferes with TH signaling, RNA-seq analysis provided no evidence that they can act as TRα1 agonists or antagonists. Their neurodevelopmental toxicity in mammals cannot be explained by an alteration of the response to TH.
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Thyroid hormones (TH) contribute to the control of adaptive thermogenesis, which is associated with both higher energy expenditure and lower body mass index. While it was clearly established that TH act directly in the target tissues to fulfill its metabolic activities, some studies have rather suggested that TH act in the hypothalamus to control these processes. This paradigm shift has subjected the topic to intense debates. This review aims to recapitulate how TH control adaptive thermogenesis and to what extent the brain is involved in this process. This is of crucial importance for the design of new pharmacological agents that would take advantage of the TH metabolic properties.
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Metabolismo Energético/fisiología , Hipotálamo/fisiología , Termogénesis/fisiología , Hormonas Tiroideas/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , HumanosRESUMEN
Recent articles show that thyroid hormone is a key determinant of regeneration. The regeneration capacity in adults of two cell types, cerebellum neurons and cardiomyocytes, disappeared during mammalian evolution. However, it persists at early stages of development. Data indicate that thyroid hormone, bound to its TRα1 nuclear receptor, defines the timing of the developmental transition which results in a loss of regenerative capacity. The identification of hormone-activated genes that are responsible for this transition is a new challenge for regenerative medicine.
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Regeneración/fisiología , Hormonas Tiroideas/fisiología , Adulto , Animales , Humanos , Mamíferos , Regeneración/efectos de los fármacos , Regeneración/genética , Hormonas Tiroideas/farmacologíaRESUMEN
Thyroid hormones are important for homeostatic control of energy metabolism and body temperature. Although skeletal muscle is considered a key site for thyroid action, the contribution of thyroid hormone receptor signaling in muscle to whole-body energy metabolism and body temperature has not been resolved. Here, we show that T3-induced increase in energy expenditure requires thyroid hormone receptor alpha 1 (TRα1 ) in skeletal muscle, but that T3-mediated elevation in body temperature is achieved in the absence of muscle-TRα1 . In slow-twitch soleus muscle, loss-of-function of TRα1 (TRαHSACre ) alters the fiber-type composition toward a more oxidative phenotype. The change in fiber-type composition, however, does not influence the running capacity or motivation to run. RNA-sequencing of soleus muscle from WT mice and TRαHSACre mice revealed differentiated transcriptional regulation of genes associated with muscle thermogenesis, such as sarcolipin and UCP3, providing molecular clues pertaining to the mechanistic underpinnings of TRα1 -linked control of whole-body metabolic rate. Together, this work establishes a fundamental role for skeletal muscle in T3-stimulated increase in whole-body energy expenditure.