PUBLICATION
Knockdown of monocarboxylate transporter 8 (mct8) disturbs brain development and locomotion in zebrafish
- Authors
- de Vrieze, E., van de Wiel, S.M., Zethof, J., Flik, G., Klaren, P.H., Arjona, F.J.
- ID
- ZDB-PUB-140513-223
- Date
- 2014
- Source
- Endocrinology 155(6): 2320-30 (Journal)
- Registered Authors
- Arjona, F.J., de Vrieze, Erik, Flik, Gert, Klaren, Peter
- Keywords
- none
- MeSH Terms
-
- Locomotion/genetics
- Locomotion/physiology
- Immunohistochemistry
- Animals, Genetically Modified
- Mice
- Brain/growth & development*
- Brain/metabolism*
- Zebrafish/genetics
- Zebrafish/growth & development*
- Zebrafish/metabolism*
- Animals
- Monocarboxylic Acid Transporters/genetics
- Monocarboxylic Acid Transporters/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 24693966 Full text @ Endocrinology
Citation
de Vrieze, E., van de Wiel, S.M., Zethof, J., Flik, G., Klaren, P.H., Arjona, F.J. (2014) Knockdown of monocarboxylate transporter 8 (mct8) disturbs brain development and locomotion in zebrafish. Endocrinology. 155(6):2320-30.
Abstract
Allan-Herndon-Dudley syndrome (AHDS) is an inherited disorder of brain development characterized by severe psychomotor retardation. This X-linked disease is caused by mutations in the monocarboxylate transporter 8 (MCT8), an important thyroid hormone (TH) transporter in brain neurons. MCT8 knockout mice lack the two major neurological symptoms of AHDS, viz. locomotor problems and cognitive impairment. The pathological mechanism explaining the symptoms is still obscure and no cure for this condition is known. The development of an animal model that carries MCT8-related neurological symptoms is warranted. We have employed morpholino-based gene knockdown to create zebrafish deficient for mct8. Knockdown of mct8 results in specific symptoms in the thyroid axis and brain. mct8-morphants showed impaired locomotor behavior and brain development. More specifically, we observed maldevelopment of the cerebellum and mid-hindbrain boundary, and apoptotic clusters in the zebrafish brain. The mRNA expression of zebrafish orthologues of mammalian thyroid stimulating hormone, thyroid hormone transporters, and deiodinases was altered in mct8 morphants. In particular, deiodinase type 3 gene expression was consistently up-regulated in zebrafish mct8 morphants. The thyroid hormone metabolite tetrac, but not triiodothyronine (T3), partly ameliorated the affected phenotype and locomotion disability of morphant larvae. Our results show that mct8 knockdown in zebrafish larvae results in disturbances in the thyroid axis, brain, and locomotion behavior, which is congruent with the clinical aspect of impaired locomotion and cognition in patients with AHDS. Taken together, zebrafish is a suitable animal model for the study of the pathophysiology of Allan-Herndon-Dudley syndrome.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping