Radial glial cell activity in disorders of thyroid hormone transport

Thyroid hormones (THs) T3 and T4 are crucial regulators of brain development and function. Cell-specific transporter proteins facilitate TH uptake and efflux across the cell membrane, and insufficient TH transport causes hypothyroidism and mental retardation. Mutations in the TH transporters monocarboxylate transporter 8 (MCT8, SLC16A2) and the organic anion-transporting polypeptide 1C1 (OATP1C1, SLCO1C1) are associated with the psychomotor retardation Allan-Herndon-Dudley syndrome (AHDS) and juvenile neurodegeneration, respectively. We established mct8 (mct8-/-) and oatp1c1 (oatp1c1-/-) mutant zebrafish as model animals for these disorders of thyroid hormone transport. These models demonstrate endocrinological, neurological, and behavioral alterations mimicking the patients` symptoms. Notably, live imaging analysis revealed that brain hypothyroidism results in structural alteration in radial glial cells (RGCs), which are progenitors of both glial and neuronal cells. Simultaneous monitoring of tail movement and genetically encoded calcium indicator showed that extensive tail movement is followed by a burst of synchronized activity of RGCs in the optic tectum of larvae. The spontaneous activity of these cells including amplitude, intensity and synchronization, was studied in mct8-/-, oatp1c1-/-, and thyroid gland-ablated larvae. The findings revealed a novel role for TH-dependent activity of RGCs in regulating behavior, and provided mechanistic and therapeutic targets to neurodevelopmental and hypothyroidism disorders.