Characterization and in vivo pharmacological rescue of a Wnt2-Gata6 pathway required for cardiac inflow tract development.
Little is understood about the molecular mechanisms underlying the morphogenesis of the posterior pole of the heart. Here we show that Wnt2 is expressed specifically in the developing inflow tract mesoderm, which generates portions of the atria and atrio-ventricular canal. Loss of Wnt2 results in defective development of the posterior pole of the heart, resulting in a phenotype resembling the human congenital heart syndrome complete common atrio-ventricular canal. The number and proliferation of posterior second heart field progenitors is reduced in Wnt2(-/-) mutants. Moreover, these defects can be rescued in a temporally restricted manner through pharmacological inhibition of Gsk-3beta. We also show that Wnt2 works in a feedforward transcriptional loop with Gata6 to regulate posterior cardiac development. These data reveal a molecular pathway regulating the posterior cardiac mesoderm and demonstrate that cardiovascular defects caused by loss of Wnt signaling can be rescued pharmacologically in vivo.
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ying
Y
Tian
Lijun
L
Yuan
Ashley M
AM
Goss
Tao
T
Wang
Jifu
J
Yang
John J
JJ
Lepore
Diane
D
Zhou
Robert J
RJ
Schwartz
Vickas
V
Patel
Ethan David
ED
Cohen
Edward E
EE
Morrisey
D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005318:Fetal Heart / Q000187:drug effects / Q000196:embryology* / Q000502:physiology*; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008955:Models, Cardiovascular; D010641:Phenotype; D011247:Pregnancy; D015398:Signal Transduction; D051154:Wnt2 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D004791:Enzyme Inhibitors; D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D051154:Wnt2 Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride