Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome

Maity-Kumar, Gandhari; Ständer, Lisa; DeAngelis, Meri; Lee, Sooyeon; Molenaar, Anna; Becker, Lore; Garrett, Lillian; Amerie, Oana V.; Hoelter, Sabine M.; Wurst, Wolfgang; Fuchs, Helmut; Feuchtinger, Annette; Gailus‐Durner, Valérie; García‐Cáceres, Cristina; Othman, Ahmed E.; Brockmann, Caroline; Schöffling, Vanessa I.; Beiser, Katja; Krude, Heiko; Mróz, Piotr; Hofmann, Susanna M.; Tuckermann, Jan; DiMarchi, Richard D.; Angelis, Martin Hrabé de; Tschöp, Matthias H.; Pfluger, Paul T.; Müller, Timo

doi:10.1016/j.molmet.2022.101616

Cited by 3 publications

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References 31 publications

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“…Impaired maternal thyroid hormone signaling during mammalian neurodevelopment caused by mutations in thyroid hormone receptors giving resistance to T3 ( 71 – 74 ), congenital hypothyroid athyroid pax8 mutants, or double-knockdown Mct8 / Oatp1c1 ( 40 , 75 , 76 ), present similar cellular effects to the ones observed in zebrafish mct8 morphant embryos ( ( 27 , 45 ), present study). In the developing cortex of Mct8 / Octp1c1 double-KO embryonic mice ( 40 , 41 , 76 ), Hr and gad67 (respectively, homologs of zebrafish her2 and gad1b ) expressing cells are mostly lost in the dorsal region, suggesting that in vertebrates MTH is an essential factor for dorsal specification of neuronal cell identities. Most notably, inhibitory neuron development seems particularly dependent on MTH action in mice ( 41 , 76 ) and zebrafish ( 27 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

“…In the developing cortex of Mct8 / Octp1c1 double-KO embryonic mice ( 40 , 41 , 76 ), Hr and gad67 (respectively, homologs of zebrafish her2 and gad1b ) expressing cells are mostly lost in the dorsal region, suggesting that in vertebrates MTH is an essential factor for dorsal specification of neuronal cell identities. Most notably, inhibitory neuron development seems particularly dependent on MTH action in mice ( 41 , 76 ) and zebrafish ( 27 , 45 ). In rat embryos, T3 deficiency decreases the proliferation and delays the maturation of the precursors of cerebellar GABAergic interneurons, with effects on the number of mature GABAergic neurons and GABAergic terminals ( 76 , 77 ).…”

Section: Discussionmentioning

confidence: 99%

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In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

Silva

Campinho

2023

Front. Endocrinol.

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BackgroundMaternally derived thyroid hormone (T3) is a fundamental factor for vertebrate neurodevelopment. In humans, mutations on the thyroid hormones (TH) exclusive transporter monocarboxylic acid transporter 8 (MCT8) lead to the Allan-Herndon-Dudley syndrome (AHDS). Patients with AHDS present severe underdevelopment of the central nervous system, with profound cognitive and locomotor consequences. Functional impairment of zebrafish T3 exclusive membrane transporter Mct8 phenocopies many symptoms observed in patients with AHDS, thus providing an outstanding animal model to study this human condition. In addition, it was previously shown in the zebrafish mct8 KD model that maternal T3 (MTH) acts as an integrator of different key developmental pathways during zebrafish development.MethodsUsing a zebrafish Mct8 knockdown model, with consequent inhibition of maternal thyroid hormones (MTH) uptake to the target cells, we analyzed genes modulated by MTH by qPCR in a temporal series from the start of segmentation through hatching. Survival (TUNEL) and proliferation (PH3) of neural progenitor cells (dla, her2) were determined, and the cellular distribution of neural MTH-target genes in the spinal cord during development was characterized. In addition, in-vivo live imaging was performed to access NOTCH overexpression action on cell division in this AHDS model. We determined the developmental time window when MTH is required for appropriate CNS development in the zebrafish; MTH is not involved in neuroectoderm specification but is fundamental in the early stages of neurogenesis by promoting the maintenance of specific neural progenitor populations. MTH signaling is required for developing different neural cell types and maintaining spinal cord cytoarchitecture, and modulation of NOTCH signaling in a non-autonomous cell manner is involved in this process.DiscussionThe findings show that MTH allows the enrichment of neural progenitor pools, regulating the cell diversity output observed by the end of embryogenesis and that Mct8 impairment restricts CNS development. This work contributes to the understanding of the cellular mechanisms underlying human AHDS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

Silva

Campinho

2023

Front. Endocrinol.

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“…Secondly, the dose of Triac was on the lower side of the recommended dose for humans and dose adjustment was not performed. More recently, MCT8/OATP1C1 DKO mice were validated to be a valuable model organism for the preclinical evaluation of drugs as they exhibit both peripheral and neurocognitive phenotype ( 17 ). Previous studies starting Triac as early as possible on the first day of life in MCT8/OATP1C1 DKO mice report a recuperated neuromotor phenotype ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Impact of Early Intervention with Triiodothyroacetic Acid on Peripheral and Neurodevelopmental Findings in a Boy with MCT8 Deficiency

Ünsal,

Hayran

2023

Jcrpe

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Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disorder characterized by peripheral thyrotoxicosis and severe cognitive and motor disability due to cerebral hypothyroidism. 3,3’,5-triiodothyroacetic acid (Triac) was shown to improve peripheral thyrotoxicosis but data on neurodevelopmental outcome are scarce. We present a case of MCT8 deficiency and the experience with Triac focusing on change in neurodevelopmental and peripheral features. A five-month-old boy was referred because of feeding difficulty, central hypotonia and global developmental delay. Despite six months of physiotherapy, physical developmental milestones did not improve, and distal muscle tone was increased. A hemizygous pathogenic variant in SLC16A2 was found and MCT8 deficiency was confirmed at 19-months. Thyroid stimulating hormone was 2.83 mIU/mL, free thyroxine 6.24 pmol/L (N=12-22) and free triiodothyronine (FT3) 15.65pmol/L (N=3.1-6.8). He had tachycardia, blood pressure and transaminases were elevated. Triac was started at 21-months. Two weeks after treatment, FT3 dramatically decreased, steady normal serum FT3 was achieved at 28-months. Assessment of neurodevelopmental milestones and signs of hyperthyroidism were evaluated at baseline, 6 months and 12 months after treatment. Signs of hyperthyroidism were improved by 6 months. Developmental composite scores of Bayley Scales of Infant Developmental 3 rd Edition remained the same but important developmental milestones (head control, recognition of caregiver, response to his name) were attained, regression in the attained milestones were not observed. Initial dose, management protocol for Triac and research into its efficacy on neurodevelopmental signs in MCT8 deficiency are progressing. This case presents evidence that Triac may resolve peripheral thyrotoxicosis successfully and may slow neurodevelopmental regression, while some developmental milestones were achieved after one year of treatment.

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A Highly Selective Fluorescent Probe for Monitoring the Thyroid Hormone Transporter Activity in Mammalian Cells

Giri,

Govindaraj,

Kumar

et al. 2024

Chemistry A European J

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Monocarboxylate transporter 8 (MCT8) is a trans‐membrane transporter, which mediates the cellular delivery of thyroid hormones, L‐thyroxine (T4) and 3,5,3 '‐triiodo‐L‐thyronine (T3). In humans, the MCT8 protein is encoded by the SLC16A2 gene and mutations in the transporter cause a genetic neurological disorder known as Allan‐Herndon‐Dudley syndrome (AHDS). MCT8 deficiency leads to impaired transport of thyroid hormones in the brain. Radiolabelled T4 and T3 or LC/MS‐MS methods have been used to monitor the thyroid hormone uptake through MCT8. Herein, we developed a fluorescent based assay to monitor the thyroid hormone uptake through MCT8. A dansyl‐based fluorescent probe having L‐thyroxine moiety is found to be highly selective towards MCT8 in living cells. The high selectivity of the probe towards MCT8 can be attributed to the halogen bond‐mediated recognition by the transporter protein. The presence of a free carboxylic acid group is essential for the specificity of the probe towards MCT8. Additionally, the selectivity of the probe for MCT8 is abolished upon esterification of the carboxylic group. Similarly, MCT8 does not recognize the probe when it contains a free amine group.

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Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome

Cited by 3 publications

References 31 publications

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

Impact of Early Intervention with Triiodothyroacetic Acid on Peripheral and Neurodevelopmental Findings in a Boy with MCT8 Deficiency

A Highly Selective Fluorescent Probe for Monitoring the Thyroid Hormone Transporter Activity in Mammalian Cells

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