Abstract
ABSTRACTHypomyelination 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.
Highlights
Leukodystrophies are a group of genetic disorders that affect the central nervous system (CNS) by altering the development and maintenance of myelin
Loss of Mct8 alters the expression levels of markers for oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes The expression of myelin-related genes in zebrafish is first detected 2 days post-fertilization and the onset of myelination occurs at 3 dpf, mainly in the ventral hindbrain and the spinal cord (SC) (Brösamle and Halpern, 2002; Buckley et al, 2010a; Kirby et al, 2006)
Whereas the mRNA levels of sox10 did not change in mct8−/− embryos, the mRNA levels of olig2 increased by 22% [t=−6.69, degrees of freedom (d.f.)=14, P
Summary
Leukodystrophies are a group of genetic disorders that affect the central nervous system (CNS) by altering the development and maintenance of myelin. Myelination is a process in which specialized glial cells – oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS) – send extensions of fatty substance and form. Received 21 July 2016; Accepted 19 September 2016 myelin sheaths that wrap axons. This insulation is vital for rapid electrical conduction and information processing (Hartline and Colman, 2007; Raphael and Talbot, 2011; Czopka, 2016). The functional myelin-producing cells are differentiated from oligodendrocyte progenitor cells (OPCs), which are active primarily during embryonic development and in juveniles and adults (Dawson et al, 2003). Hypomyelination disorders are extensively studied, the pathogenic mechanism is unclear and treatments are limited
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