Supplemental Material ( Figure, Table, Video)

Thyroid dysgenesis (TD) is the common pathogenic mechanism of congenital hypothyroidism (CH). In addition, known pathogenic genes are limited to those that are directly involved in thyroid development. To identify additional candidate pathogenetic genes, we performed forward genetic screening for TD in zebrafish, followed by positional cloning. The candidate gene was confirmed in vitro using the Nthy-ori 3.1 cell line and in vivo using a zebrafish model organism. We obtained a novel zebrafish line with thyroid dysgenesis and identified the candidate pathogenetic gene taf1 by positional cloning. Further molecular studies revealed that taf1 was needed for the proliferation of thyroid follicular cells by binding to the NOTCH1 promoter region. Knockdown of TAF1 impaired the proliferation and maturation of thyroid cells, thereby leading to thyroid dysplasia. This study showed that TAF1 promoted Notch signaling and that this association played a pivotal role in thyroid development.

甲状腺发育不全（Thyroid dysgenesis, TD）是先天性甲状腺功能减退症（Congenital hypothyroidism, CH）的常见致病机制。目前已知的致病基因仅局限于直接参与甲状腺发育的基因范畴。为鉴定额外的候选致病基因，我们在斑马鱼中开展了针对TD的正向遗传筛选，并结合位置克隆技术进行后续分析。我们通过Nthy-ori 3.1细胞系完成体外验证，利用斑马鱼模式生物完成体内验证。我们成功获得一株新型甲状腺发育不全斑马鱼品系，并通过位置克隆技术鉴定出候选致病基因taf1。进一步的分子实验揭示，taf1可通过结合NOTCH1启动子区域，调控甲状腺滤泡细胞的增殖过程。敲低TAF1会损害甲状腺细胞的增殖与成熟，进而引发甲状腺发育不全。本研究证实，TAF1可促进Notch信号通路，且该调控关联在甲状腺发育过程中发挥关键作用。