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。截至目前，已知的致病基因仅局限于直接参与甲状腺发育的相关基因。为挖掘更多潜在致病基因，本研究以斑马鱼为模型开展TD的正向遗传筛选（forward genetic screening），随后通过位置克隆（positional cloning）技术展开后续研究。研究团队通过Nthy-ori 3.1细胞系开展体外实验（in vitro）验证，并借助斑马鱼模型完成体内验证（in vivo），以确认候选致病基因。本研究成功构建了一株携带甲状腺发育不全表型的新型斑马鱼品系，并通过位置克隆技术鉴定出候选致病基因taf1。后续分子机制研究显示，taf1可通过结合NOTCH1启动子区域（promoter region），调控甲状腺滤泡细胞（thyroid follicular cells）的增殖过程。敲低（Knockdown）TAF1的表达会抑制甲状腺细胞的增殖与成熟，进而引发甲状腺发育异常。本研究证实，TAF1可激活Notch信号通路（Notch signaling），二者的协同调控作用在甲状腺发育过程中发挥关键作用。