Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

Krieger, Teresa G; Moran, Carla; Frangini, Alberto; Visser, W. Edward; Schoenmakers, Erik; Muntoni, F.; Clark, Chris A.; Gadian, David G.; Chong, W.K.; Kuczynski, Adam M.; Dattani, Mehul; Lyons, Greta; Efthymiadou, Alexandra; Varga-Khadem, Faraneh; Simons, Benjamin D.; Chatterjee, Krishna; Livesey, Frederick J.

doi:10.1073/pnas.1908762116

Cited by 34 publications

(19 citation statements)

References 53 publications

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“…To date, about 20 missense and frameshift mutations of THRA have been described [121,[136][137][138][139][140]. Clinical features of patients include many symptoms commonly present in hypothyroidism, such as bradycardia, constipation, skeletal dysplasia (macrocephaly, late fontanelle closure, and epiphyseal dysgenesis), delayed bone growth and psychomotor development, and intellectual disability [72,121,141]. In other words, the pathological signs involve those tissue that normally rely on TRα.…”

Section: Th Resistancementioning

confidence: 99%

“…Moreover, a de novo missense mutation (R384C) in TRα1 was found in a patient affected by an autism spectrum disorder [143]. Recently, it has been reported that TRα1 is required for normal neural progenitor cell proliferation in human cerebral cortical development; as a consequence, mutations in the TRA gene cause a reduction of brain size and intellectual disability [141].…”

Section: Th Resistancementioning

confidence: 99%

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Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

Giammanco

Schiera

Liegro

2020

IJMS

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Since the realization that the cellular homologs of a gene found in the retrovirus that contributes to erythroblastosis in birds (v-erbA), i.e. the proto-oncogene c-erbA encodes the nuclear receptors for thyroid hormones (THs), most of the interest for THs focalized on their ability to control gene transcription. It was found, indeed, that, by regulating gene expression in many tissues, these hormones could mediate critical events both in development and in adult organisms. Among their effects, much attention was given to their ability to increase energy expenditure, and they were early proposed as anti-obesity drugs. However, their clinical use has been strongly challenged by the concomitant onset of toxic effects, especially on the heart. Notably, it has been clearly demonstrated that, besides their direct action on transcription (genomic effects), THs also have non-genomic effects, mediated by cell membrane and/or mitochondrial binding sites, and sometimes triggered by their endogenous catabolites. Among these latter molecules, 3,5-diiodo-L-thyronine (3,5-T2) has been attracting increasing interest because some of its metabolic effects are similar to those induced by T3, but it seems to be safer. The main target of 3,5-T2 appears to be the mitochondria, and it has been hypothesized that, by acting mainly on mitochondrial function and oxidative stress, 3,5-T2 might prevent and revert tissue damages and hepatic steatosis induced by a hyper-lipid diet, while concomitantly reducing the circulating levels of low density lipoproteins (LDL) and triglycerides. Besides a summary concerning general metabolism of THs, as well as their genomic and non-genomic effects, herein we will discuss resistance to THs and the possible mechanisms of action of 3,5-T2, also in relation to its possible clinical use as a drug.

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Section: Th Resistancementioning

confidence: 99%

Section: Th Resistancementioning

confidence: 99%

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

Giammanco

Schiera

Liegro

2020

IJMS

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“…Two intriguing studies using novel models of thyroid hormone receptor alpha ( THRA ) mutations, which cause thyroid hormone resistance syndrome (RTH), were published in 2020. Krieger et al [ 1 ] demonstrated the essential actions of thyroid hormone receptor alpha (TRα) on the normal development of the human cerebral cortex. The authors previously reported that adult patients with RTH had intellectual impairments, especially affecting nonverbal IQ and delayed sensorimotor processing [ 2 ].…”

Section: New Understandings Of Thyroid Hormone Actions and Signaling mentioning

confidence: 99%

“…Indeed, these findings were consistent with those of a mouse model with a mutant variant of TRα1, which showed a range of central nervous system abnormalities [ 3 ], but the cellular mechanisms of the impacts of THRA (the gene encoding TRα) on neural development remained unclear. Krieger et al [ 1 ], using THRA mutant patient-derived induced pluripotent stem cell (iPS) models in combination with a quantitative lineage analysis, gene expression analysis, and novel assays of neuro-epithelium formation, showed that THRA regulates the balance between progenitor self-renewal and neurogenesis, thereby affecting the overall brain mass and especially the cortex. A structural modeling study of the ligand-binding domain of TRα1 demonstrated that the THRA mutation facilitates corepressor binding.…”

Section: New Understandings Of Thyroid Hormone Actions and Signaling mentioning

confidence: 99%

Best Achievements in Translational and Basic Thyroidology in 2020

Cho

Park

2021

Endocrinol Metab

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This review discusses articles published in 2020 that presented noteworthy achievements in translational and basic thyroidology. Previously unresolved questions about thyroid hormone receptor actions and signaling mechanisms were answered using various novel in vitro and in vivo models. Using high resolution cryo-electron microscopy, the fine functional structure of thyroglobulin was demonstrated, and new insights into the pathogenesis of thyroid disease were achieved, with a focus on research into thyroid-disrupting chemicals and the gut microbiome. Novel therapeutic approaches were tried in the field of advanced thyroid cancer treatments.

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“…Thyroid hormone is a key endocrine signal conserved in all vertebrates, including humans, regulating many homeostatic processes such as growth, reproduction and energy metabolism. TH also regulates CNS development ( Gothié et al, 2017 ) by influencing all neurodevelopmental processes, including cell cycle progression, fate choice, migration, differentiation, axo- and synaptogenesis, and myelination ( Zoeller and Rovet, 2004 ; Moog et al, 2017 ; Krieger et al, 2019 ; Vancamp et al, 2020 ). Under pathophysiological conditions, TH acts on each of these processes, promoting regeneration in the adult fish brain that retained large numbers of NSCs ( Grandel et al, 2006 ; Bhumika and Darras, 2014 ).…”

Section: The Potential Of Thyroid Hormone As a Pro-repair Cuementioning

confidence: 99%

Thyroid Hormone and Neural Stem Cells: Repair Potential Following Brain and Spinal Cord Injury

Vancamp¹,

Butruille²,

Demeneix³

et al. 2020

Front. Neurosci.

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Neurodegenerative diseases are characterized by chronic neuronal and/or glial cell loss, while traumatic injury is often accompanied by the acute loss of both. Multipotent neural stem cells (NSCs) in the adult mammalian brain spontaneously proliferate, forming neuronal and glial progenitors that migrate toward lesion sites upon injury. However, they fail to replace neurons and glial cells due to molecular inhibition and the lack of pro-regenerative cues. A major challenge in regenerative biology therefore is to unveil signaling pathways that could override molecular brakes and boost endogenous repair. In physiological conditions, thyroid hormone (TH) acts on NSC commitment in the subventricular zone, and the subgranular zone, the two largest NSC niches in mammals, including humans. Here, we discuss whether TH could have beneficial actions in various pathological contexts too, by evaluating recent data obtained in mammalian models of multiple sclerosis (MS; loss of oligodendroglial cells), Alzheimer's disease (loss of neuronal cells), stroke and spinal cord injury (neuroglial cell loss). So far, TH has shown promising effects as a stimulator of remyelination in MS models, while its role in NSC-mediated repair in other diseases remains elusive. Disentangling the spatiotemporal aspects of the injury-driven repair response as well as the molecular and cellular mechanisms by which TH acts, could unveil new ways to further exploit its proregenerative potential, while TH (ant)agonists with cell type-specific action could provide safer and more target-directed approaches that translate easier to clinical settings.

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Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

Cited by 34 publications

References 53 publications

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

Best Achievements in Translational and Basic Thyroidology in 2020

Thyroid Hormone and Neural Stem Cells: Repair Potential Following Brain and Spinal Cord Injury

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