ZFIN ID: ZDB-PUB-171004-6
Thyroid hormone regulates hematopoiesis via the TR-KLF9 axis
Zhang, Y., Xue, Y., Cao, C., Huang, J., Hong, Q., Hai, T., Jia, Q., Wang, X., Qin, G., Yao, J., Wang, X., Zheng, Q., Zhang, R., Li, Y., Luo, A., Zhang, N., Shi, G., Wang, Y., Ying, H., Liu, Z., Wang, H., Meng, A., Zhou, Q., Wei, H., Liu, F., Zhao, J.
Date: 2017
Source: Blood   130(20): 2161-2170 (Journal)
Registered Authors: Liu, Feng, Meng, Anming
Keywords: none
MeSH Terms:
  • Animals
  • Congenital Hypothyroidism/genetics
  • Congenital Hypothyroidism/physiopathology*
  • Disease Models, Animal*
  • Dual Oxidases/genetics
  • Ethylnitrosourea
  • Gene Expression Regulation
  • Genes, Recessive
  • Hematopoiesis*
  • Hydrogen Peroxide/metabolism
  • Kruppel-Like Transcription Factors/metabolism*
  • Metabolic Networks and Pathways
  • Mutagenesis, Site-Directed
  • Mutation
  • Receptors, Thyroid Hormone/metabolism*
  • Swine*
  • Thymus Gland
  • Thyroid Hormones/physiology*
  • Whole Exome Sequencing
  • Zebrafish
  • Zebrafish Proteins/metabolism
PubMed: 28972010 Full text @ Blood
Congenital hypothyroidism (CH) is one of the most prevalent endocrine diseases, for which the underlying mechanisms remain unknown; it is often accompanied by anemia and immunodeficiency in patients. Here, we created a severe CH model together with anemia and T lymphopenia to mimic the clinical features of hypothyroid patients by ethylnitrosourea (ENU) mutagenesis in Bama miniature pigs. A novel recessive c.1226A>G transition of the dual oxidase 2 (DUOX2) gene was identified as the causative mutation. This mutation hindered the production of hydrogen peroxide (H2O2) and thus contributed to thyroid hormone (TH) synthesis failure. Transcriptome sequencing analysis of the thymuses showed that Krüppel-like factor 9 (KLF9) was predominantly downregulated in hypothyroid mutants. KLF9 was verified to be directly regulated by TH in a TH receptor (TR)-dependent manner both in vivo and in vitro. Furthermore, knockdown of klf9 in zebrafish embryos impaired hematopoietic development including erythroid maturation and T lymphopoiesis. Our findings suggest that the TR-KLF9 axis is responsible for the hematopoietic dysfunction and might be exploited for the development of novel therapeutic interventions for thyroid diseases.