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

TY - JOUR

T1 - Noonan and LEOPARD syndrome Shp2 variants induce heart displacement defects in zebrafish

AU - Bonetti, Monica

AU - Paardekooper Overman, Jeroen

AU - Tessadori, Federico

AU - Noël, Emily

AU - Bakkers, Jeroen

AU - den Hertog, Jeroen

PY - 2014/5

Y1 - 2014/5

N2 - 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.

AB - 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.

KW - Animals

KW - Benzamides

KW - Body Patterning

KW - Cell Movement

KW - Cilia

KW - Embryo, Nonmammalian

KW - Heart Defects, Congenital

KW - Heart Function Tests

KW - Humans

KW - LEOPARD Syndrome

KW - Mitogen-Activated Protein Kinase Kinases

KW - Mutation

KW - Myocytes, Cardiac

KW - Noonan Syndrome

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 11

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1242/dev.106310

DO - 10.1242/dev.106310

M3 - Article

C2 - 24718990

SN - 0950-1991

VL - 141

SP - 1961

EP - 1970

JO - Development

JF - Development

IS - 9

ER -