Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome

Balow, S.A., Pierce, L.X., Zentner, G.E., Conrad, P.A., Davis, S., Sabaawy, H.E., McDermott, B.M., and Scacheri, P.C.
Developmental Biology   382(1): 57-69 (Journal)
Registered Authors
McDermott Jr., Brian M., Sabaawy, Hatem
CHARGE syndrome, chd7, fbxl10, zebrafish, cell proliferation, rRNA
MeSH Terms
  • Animals
  • Base Sequence
  • CHARGE Syndrome/metabolism
  • CHARGE Syndrome/pathology*
  • Cartilage/drug effects
  • Cartilage/embryology
  • Cartilage/metabolism
  • Cell Cycle/drug effects
  • Cell Cycle/genetics
  • Cell Proliferation/drug effects
  • DNA Helicases/metabolism*
  • DNA-Binding Proteins/metabolism*
  • Disease Models, Animal
  • Embryonic Development/drug effects
  • Embryonic Development/genetics
  • F-Box Proteins/genetics
  • F-Box Proteins/metabolism*
  • Gene Expression Regulation, Developmental/drug effects
  • Gene Knockdown Techniques*
  • Gene Targeting
  • Humans
  • Jumonji Domain-Containing Histone Demethylases/genetics
  • Jumonji Domain-Containing Histone Demethylases/metabolism*
  • Molecular Sequence Data
  • Morpholinos/pharmacology*
  • Neural Crest/drug effects
  • Neural Crest/embryology
  • Neural Crest/metabolism
  • Phenotype
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • RNA, Ribosomal/genetics
  • RNA, Ribosomal/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
23920116 Full text @ Dev. Biol.

CHARGE syndrome is a sporadic autosomal-dominant genetic disorder characterized by a complex array of birth defects so named for its cardinal features of ocular coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Approximately two-thirds of individuals clinically diagnosed with CHARGE syndrome have heterozygous loss-of-function mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7), an ATP-dependent chromatin remodeler. To examine the role of Chd7 in development, a zebrafish model was generated through morpholino (MO)-mediated targeting of the zebrafish chd7 transcript. High doses of chd7 MO induce lethality early in embryonic development. However, low dose-injected embryos are viable, and by 4 days post-fertilization, morphant fish display multiple defects in organ systems analogous to those affected in humans with CHARGE syndrome. The chd7 morphants show elevated expression of several potent cell-cycle inhibitors including ink4ab (p16/p15), p21 and p27, accompanied by reduced cell proliferation. We also show that Chd7 is required for proper organization of neural crest-derived craniofacial cartilage structures. Strikingly, MO-mediated knockdown of the jumonji domain-containing histone demethylase fbxl10/kdm2bb, a repressor of ribosomal RNA (rRNA) genes, rescues cell proliferation and cartilage defects in chd7 morphant embryos and can lead to complete rescue of the CHARGE syndrome phenotype. These results indicate that CHARGE-like phenotypes in zebrafish can be mitigated through modulation of fbxl10 levels and implicate FBXL10 as a possible therapeutic target in CHARGE syndrome.

Genes / Markers
Figure Gallery
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes