Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Iwayama, Hideyuki; Liao, Xiao Hui; Braun, Lyndsey; Bárez-López, Soledad; Kaspar, Brian K.; Weiss, Roy E.; Dumitrescu, Alexandra M.; Guadaño-Ferraz, Ana; Refetoff, Samuel

doi:10.1089/thy.2016.0060

Cited by 36 publications

(33 citation statements)

References 26 publications

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“…Furthermore the function of MCT8 mutants is also dependent on the cellular context 31 . The only known function of MCT8 is facilitated cellular transport of iodothyronines across the plasma membrane and no other substrates have been described in vertebrates 32 , 33 and a recent study confirmed that MCT8 lacks constitutive activity 34 . We have previously shown that the zebrafish MCT8 knockdown displayed locomotor, cellular and molecular changes congruent with the human neurological symptoms of AHDS 15 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Silva

Louro

Trindade

et al. 2017

Sci Rep

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Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.

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Section: Discussionmentioning

confidence: 99%

Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Silva

Louro

Trindade

et al. 2017

Sci Rep

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“…These results suggest that, although Mct8 is also expressed in neurons and glial cells, endothelial-cell-specific expression of Mct8 makes the BBB permeable to TH and enables TH access into the brain, which is sufficient to induce myelination. Recently, intravenous injection of adeno-associated virus 9 driving the expression of human MCT8 was shown to increase T3 content in the mouse brain (Iwayama et al, 2016). Further studies that test the effect of vascular Mct8 expression on neurons and glial cells in various brain regions in mct8 −/− larvae and mouse models are required in order to evaluate this treatment approach.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish

Zada

Tovin

Lerer-Goldshtein

et al. 2016

Disease Models &Amp; Mechanisms

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Hypomyelination is a key symptom of Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8 (monocarboxylate transporter 8). AHDS is characterized by severe intellectual deficiency, neuromuscular impairment and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelination, we developed an mct8 mutant (mct8−/−) zebrafish model. The quantification of genetic markers for oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes revealed reduced differentiation of OPCs into oligodendrocytes in mct8−/− larvae and adults. Live imaging of single glial cells showed that the number of oligodendrocytes and the length of their extensions are reduced, and the number of peripheral Schwann cells is increased, in mct8−/− larvae compared with wild type. Pharmacological analysis showed that TH analogs and clemastine partially rescued the hypomyelination in the CNS of mct8−/− larvae. Intriguingly, triiodothyronine (T3) treatment rescued hypomyelination in mct8−/− embryos before the maturation of the blood–brain barrier (BBB), but did not affect hypomyelination in older larvae. Thus, we expressed Mct8-tagRFP in the endothelial cells of the vascular system and showed that even relatively weak mosaic expression completely rescued hypomyelination in mct8−/− larvae. These results suggest potential pharmacological treatments and BBB-targeted gene therapy that can enhance myelination in AHDS and possibly in other TH-dependent brain disorders.

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“…These barriers tightly control the influx and efflux of molecules and ions at the blood-brain interface to meet neural cell needs and to protect the brain from toxins and pathogens (Obermeier et al, 2013 ). The severe alterations present in MCT8-deficient patients (Fu et al, 2013 ) revealed the relevance of TH transporters and the importance of TH transport across brain barriers (Ceballos et al, 2009 ; Iwayama et al, 2016 ; Vatine et al, 2017 ). Studies in the rat indicated that the contribution of the choroid plexus to the total brain TH content is about 18% (Chanoine et al, 1992 ) and, since the BBB surface area is much greater than that of the choroid plexus, the BBB has been considered the major pathway for TH entry into the brain (Dratman et al, 1991 ).…”

Section: Brain Barriers and Thyroid Hormonesmentioning

confidence: 99%

Thyroid Hormone Availability and Action during Brain Development in Rodents

Bárez-López

Guadaño-Ferraz

2017

Front. Cell. Neurosci.

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Thyroid hormones (THs) play an essential role in the development of all vertebrates; in particular adequate TH content is crucial for proper neurodevelopment. TH availability and action in the brain are precisely regulated by several mechanisms, including the secretion of THs by the thyroid gland, the transport of THs to the brain and neural cells, THs activation and inactivation by the metabolic enzymes deiodinases and, in the fetus, transplacental passage of maternal THs. Although these mechanisms have been extensively studied in rats, in the last decade, models of genetically modified mice have been more frequently used to understand the role of the main proteins involved in TH signaling in health and disease. Despite this, there is little knowledge about the mechanisms underlying THs availability in the mouse brain. This mini-review article gathers information from findings in rats, and the latest findings in mice regarding the ontogeny of TH action and the sources of THs to the brain, with special focus on neurodevelopmental stages. Unraveling TH economy and action in the mouse brain may help to better understand the physiology and pathophysiology of TH signaling in brain and may contribute to addressing the neurological alterations due to hypo and hyperthyroidism and TH resistance syndromes.

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Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Cited by 36 publications

References 26 publications

Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish

Thyroid Hormone Availability and Action during Brain Development in Rodents

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