Knockdown of monocarboxylate transporter 8 (mct8) disturbs brain development and locomotion in zebrafish.
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 transporter in brain neurons. MCT8-knockout mice lack the 2 major neurological symptoms of AHDS, namely 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. The 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 orthologs of mammalian TSH, 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 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, the zebrafish is a suitable animal model for the study of the pathophysiology of AHDS.
Department of Organismal Animal Physiology (E.d.V., S.M.W.v.d.W., J.Z., G.F., P.H.M.K.), Institute for Water and Wetland Research, Faculty of Science, Radboud University Nijmegen; and Department of Otorhinolaryngology (E.d.V.) and Department of Physiology, Radboud Institute for Molecular Life Sciences (RIMLS) (F.J.A.), Radboud university medical center, 6525 AJ Nijmegen, The Netherlands.
Erik
E
de Vrieze
Sandra M W
SM
van de Wiel
Jan
J
Zethof
Gert
G
Flik
Peter H M
PH
Klaren
Francisco J
FJ
Arjona
D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D007150:Immunohistochemistry; D008124:Locomotion / Q000235:genetics / Q000502:physiology; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D027501:Monocarboxylic Acid Transporters; D029961:Zebrafish Proteins