Deficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion

Ya Fang, Jia-Ping Wan, Zheng Wang, Shi-Yang Song, Cao-Xu Zhang, Liu Yang, Qian-Yue Zhang, Chen-Yan Yan, Feng-Yao Wu, Sang-Yu Lu, Feng Sun, Bing Han, Shuang-Xia Zhao (), Mei Dong () and Huai-Dong Song ()
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Ya Fang: Shanghai Jiao Tong University School of Medicine
Jia-Ping Wan: Shanghai Jiao Tong University School of Medicine
Zheng Wang: Shanghai Jiao Tong University School of Medicine
Shi-Yang Song: Shanghai Jiao Tong University School of Medicine
Cao-Xu Zhang: Shanghai Jiao Tong University School of Medicine
Liu Yang: Shanghai Jiao Tong University School of Medicine
Qian-Yue Zhang: Shanghai Jiao Tong University School of Medicine
Chen-Yan Yan: Shanghai Jiao Tong University School of Medicine
Feng-Yao Wu: Shanghai Jiao Tong University School of Medicine
Sang-Yu Lu: Shanghai Jiao Tong University School of Medicine
Feng Sun: Shanghai Jiao Tong University School of Medicine
Bing Han: Shanghai Jiao Tong University School of Medicine
Shuang-Xia Zhao: Shanghai Jiao Tong University School of Medicine
Mei Dong: Shanghai Jiao Tong University School of Medicine
Huai-Dong Song: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.

Date: 2024
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DOI: 10.1038/s41467-024-47363-9

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