Methyltransferase like 3 promotes thyroid folliculogenesis via coordinating cell differentiation and polarization.

BACKGROUND AND OBJECTIVES: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder with largely elusive underlying mechanisms, although thyroid dysformation has been deemed as the most frequent cause. Methyltransferase like 3 (METTL3) serves as a pivotal writer for N(6)-methyladenosine (N6-methyladenosine, m(6)A) required for various organ development, but little is known about the significance of METTL3 and m(6)A modification in thyroid formation, in CH either. In this study, we aimed to clarify the new regulatory role of METTL3 in the occurrence and development of CH, and to provide new theoretical support and treatment ideas for the clinical treatment of CH. METHODS: Thyrocyte-specific Mettl3 knockout mouse model was constructed and subjected to morphological and functional analyses. Representative differentiation, polarization, and hormone synthesis factors were studied via immunohistochemistry, immunofluorescence staining, RT-qPCR, and thyroid hormone in serum were quantified. In vitro, function of Mettl3 and molecular mechanisms were further investigated through thyrocyte cells from different species via lentivirus mediated silencing and rescue experiments. RESULTS: Thyrocyte specific removal of Mettl3 caused a typical CH phenotype, with reduced thyroid hormones and body weight. Histologically, the thyroid follicle of Mettl3 deficient mice appeared as abnormally fused and enlarged structure, with significantly disturbed polarity and patterning. Mechanistically, Pax8 expression was reduced upon METTL3 loss due to damaged m(6)A modification, which resulted in compromised thyroid epithelial cell polarization, differentiation and hormone synthesis. CONCLUSIONS: Mettl3 functions as a key player of thyroid folliculogenesis and hormone secretion by coordinating thyrocyte polarization and differentiation progression, and its deficiency may lead to congenital hypothyroidism.