Axenfeld-Rieger syndrome-associated mutants of the transcription factor FOXC1 abnormally regulate NKX2-5 in model zebrafish embryos

Zhang, Q., Liang, D., Yue, Y., He, L., Li, N., Jiang, D., Hu, P., Zhao, Q.
The Journal of biological chemistry   295(33): 11902-11913 (Journal)
Registered Authors
Liang, Dong, Yue, Yunyun, Zhao, Qingshun
Axenfeld-Rieger syndrome, Congenital heart diseases, FOXC1, H9c2, NKX2-5, cardiovascular disease, heart, mutant, transcription factor, zebrafish
MeSH Terms
  • Animals
  • Anterior Eye Segment/abnormalities*
  • Cell Line
  • Disease Models, Animal
  • Eye Abnormalities/genetics*
  • Eye Diseases, Hereditary/genetics*
  • Forkhead Transcription Factors/genetics*
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Homeobox Protein Nkx-2.5/genetics*
  • Humans
  • Mutation*
  • Zebrafish/embryology*
  • Zebrafish/genetics
32631953 Full text @ J. Biol. Chem.
FOXC1 is a member of the forkhead family of transcription factors, and whose function is poorly understood. A variety of FOXC1 mutants have been identified in patients diagnosed with the autosomal dominant disease Axenfeld-Rieger syndrome, which is mainly characterized by abnormal development of the eyes, particularly those who also have accompanying congenital heart defects (CHD). However, the role of FOXC1 in CHD, and how these mutations might impact FOXC1 function, remains elusive. Our previous work provided one clue to possible function, demonstrating that zebrafish foxc1a, an orthologue of human FOXC1 essential for heart development, directly regulates the expression of nkx2.5, encoding a transcriptional regulator of cardiac progenitor cells. Abnormal expression of Nkx2-5 leads to CHD in mice and is also associated with CHD patients. Whether this link extends to the human system, however, requires investigation. In this study, we demonstrate that FOXC1 does regulate human NKX2-5 expression in a dose-dependent manner via direct binding to its proximal promoter. A comparison of FOXC1 mutant function in the rat cardiac cell line H9c2 and zebrafish embryos suggested that the zebrafish embryos might serve as a more representative model system than the H9c2 cells. Finally, we noted that three of the Axenfeld-Rieger syndrome FOXC1 mutations tested increased whereas a fourth repressed the expression of NKX2-5 These results imply that mutant FOXC1s might play etiological roles in CHD by abnormally regulating NKX2-5 in the patients. And zebrafish embryos can serve as a useful in vivo platform for rapidly evaluating disease-causing roles of mutated genes.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes