Noonan and LEOPARD syndrome Shp2 variants induce heart displacement defects in zebrafish

Bonetti, M., Paardekooper Overman, J., Tessadori, F., Noël, E., Bakkers, J., den Hertog, J.
Development (Cambridge, England)   141: 1961-70 (Journal)
Registered Authors
Bakkers, Jeroen, den Hertog, Jeroen, Noël, Emily
LEOPARD syndrome, MAPK, Noonan syndrome, Shp2, Zebrafish
MeSH Terms
  • Animals
  • Benzamides/pharmacology
  • Body Patterning/drug effects
  • Cell Movement/drug effects
  • Cilia/drug effects
  • Cilia/metabolism
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/enzymology
  • Embryo, Nonmammalian/pathology
  • Heart Defects, Congenital/embryology
  • Heart Defects, Congenital/genetics*
  • Heart Defects, Congenital/physiopathology
  • Heart Function Tests
  • Humans
  • LEOPARD Syndrome/enzymology
  • LEOPARD Syndrome/genetics*
  • Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases/metabolism
  • Mutation/genetics*
  • Myocytes, Cardiac/drug effects
  • Myocytes, Cardiac/metabolism
  • Myocytes, Cardiac/pathology
  • Noonan Syndrome/enzymology
  • Noonan Syndrome/genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
  • Zebrafish/embryology*
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
24718990 Full text @ Development
Germline mutations in PTPN11, encoding Shp2, cause Noonan syndrome (NS) and LEOPARD syndrome (LS), two developmental disorders that are characterized by multiple overlapping symptoms. Interestingly, Shp2 catalytic activity is enhanced by NS mutations and reduced by LS mutations. Defective cardiac development is a prominent symptom of both NS and LS, but how the Shp2 variants affect cardiac development is unclear. Here, we have expressed the most common NS and LS Shp2-variants in zebrafish embryos to investigate their role in cardiac development in vivo. Heart function was impaired in embryos expressing NS and LS variants of Shp2. The cardiac anomalies first occurred during elongation of the heart tube and consisted of reduced cardiomyocyte migration, coupled with impaired leftward heart displacement. Expression of specific laterality markers was randomized in embryos expressing NS and LS variants of Shp2. Ciliogenesis and cilia function in Kupffer's vesicle was impaired, likely accounting for the left/right asymmetry defects. Mitogen-activated protein kinase (MAPK) signaling was activated to a similar extent in embryos expressing NS and LS Shp2 variants. Interestingly, inhibition of MAPK signaling prior to gastrulation rescued cilia length and heart laterality defects. These results suggest that NS and LS Shp2 variant-mediated hyperactivation of MAPK signaling leads to impaired cilia function in Kupffer's vesicle, causing left-right asymmetry defects and defective early cardiac development.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes