Thyroid hormones drive central nervous system remodelling during flatfish metamorphosis

Flatfish metamorphosis is an abrupt post-embryonic transformation driven by thyroid hormones (THs), in which a bilaterally symmetric pelagic larvae becomes an asymmetric benthic juvenile. While the craniofacial changes associated with eye migration during metamorphosis are well documented, the role of THs in central nervous system (CNS) remodelling remains poorly understood. Here we investigated the role of THs on CNS remodelling during metamorphosis of the flatfish, Solea senegalensis, by integrating high-throughput transcriptomic analysis with experimental manipulation of TH availability using an inhibitor of hormone synthesis, methimazole (MMI) or exogenous T4. Transcriptome profiling revealed 567 differentially expressed gene transcripts associated with TH-levels involved in CNS development, neuronal and glial differentiation, migration, myelination and metabolism. Key CNS-related factors such as klf9, sox9, mbp, and plp were strongly down-regulated in MMI-treated larvae. Cell proliferation assays further demonstrated increased interocular neural proliferation under hypothyroidism, consistent with impaired differentiation. Region-specific analyses of the head and body uncovered distinct patterns of TH signalling involving dio2, dio3, thra, thrb, and mct8, underscoring the spatial complexity of endocrine regulation. These results highlight that THs are crucial for both morphological remodelling and CNS plasticity during flatfish metamorphosis, underscoring their conserved role in vertebrate brain development.