Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish

Liu, Z.Z., Wang, Z.L., Choi, T.I., Huang, W.T., Wang, H.T., Han, Y.Y., Zhu, L.Y., Kim, H.T., Choi, J.H., Lee, J.S., Kim, H.G., Zhao, J., Chen, Y., Lu, Z., Tian, X.L., Pan, B.X., Li, B.M., Kim, C.H., Xu, H.
The American journal of pathology   188(4): 1043-1058 (Journal)
Registered Authors
Choi, Jung-Hwa, Kim, Cheol-Hee, Kim, Hyun-Taek
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Apoptosis/drug effects
  • Base Sequence
  • Bone Morphogenetic Proteins/metabolism
  • Branchial Region/drug effects
  • Branchial Region/embryology
  • Cell Movement/drug effects
  • Cell Proliferation/drug effects
  • Chemokines/metabolism
  • DNA Helicases/deficiency
  • DNA Helicases/metabolism*
  • DNA-Binding Proteins/deficiency
  • DNA-Binding Proteins/metabolism*
  • Embryo, Nonmammalian/metabolism
  • Epithelial Cells/metabolism
  • Forkhead Transcription Factors/metabolism
  • Hematopoietic Stem Cells/metabolism
  • Morpholinos/pharmacology
  • Mutation/genetics
  • Neural Crest/pathology
  • Organogenesis*
  • Phenotype
  • Signal Transduction
  • T-Lymphocytes/cytology*
  • Thymus Gland/cytology*
  • Thymus Gland/growth & development*
  • Zebrafish/embryology
  • Zebrafish/metabolism*
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/metabolism*
29353058 Full text @ Am. J. Pathol.
CHARGE syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T-cells have been noted in CHARGE syndrome. However, the mechanisms underlying T-lymphopenia are largely unexplored. Here, we observed dramatic decrease of T cells in both chd7-knockdown and -knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T cell decrease. Further analysis demonstrated that both the organogenesis and homing function of the thymus were seriously impaired. Chd7 might regulate thymus organogenesis through modulating the development of both neural crest cell-derived mesenchyme and pharyngeal endoderm-derived thymic epithelial cells. The expression of foxn1, a central regulator of thymic epithelium, was remarkably down-regulated in the pharyngeal region in chd7-deficient embryos. Moreover, the T-cell reduction in chd7-deficient embryos was partially rescued by overexpressing foxn1, suggesting that restoring thymic epithelium may be a potential therapeutic strategy for treating immunodeficiency in CHARGE syndrome. Collectively, the results indicated that chd7 was critical for thymic development and T-lymphopenia in CHARGE syndrome may be mainly attributed to the defects of thymic organogenesis. The current finding may benefit the diagnosis and therapy of T-lymphopenia and immunodeficiency in CHARGE syndrome.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes