High environmental levels of thyroxine altered Müller glia-derived progenitor cell proliferation, cell death, pluripotency gene expression and neurogenesis in the retina of zebrafish

The zebrafish is a useful model organism in biomedical research. Its remarkable capacity to regenerate neurons makes this species ideal for studying mechanisms that can pave the way for inducing regeneration in the adult mammalian nervous system. The zebrafish retina regenerates via reprogramming of multipotent Müller glia (MMG). Thyroid hormones (TH) are crucial in the nervous system development and retinogenesis. We aimed to investigate whether excess TH signaling affected MMG proliferation, cell death and neurogenesis. Retinal lesions were induced via intravitreal injections of ouabain or CoCl2. Zebrafish were treated with 300 μg/L thyroxine (T4) or vehicle in the aquarium water for 2, 8, 25, and 60 days. T4 treatment initially inhibited and subsequently increased MMG-derived progenitor cell proliferation. Short-term excess T4 signaling inhibited microglia activation. High levels of T4 caused significant increases in the expression of reprogramming genes. Prolonged excess T4 signaling modified the transcriptional expression of markers for bipolar, MG, rod, cone, ganglion, and horizontal cells. Chronic TH excess increased apoptosis, which counteracted progenitor proliferation and prevented regeneration. Excess TH promoted red-cone genesis and intensified gliosis. Injured retinas treated chronically with TH emulate changes observed in human hyperthyroidism-induced retinopathies. Excess T4 induced regeneration in undamaged retinas, overpacing metabolic damage.