Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors.
GATA-family transcription factors are critical to the development of diverse tissues. In particular, GATA-4 has been implicated in formation of the vertebrate heart. As the mouse Gata-4 knock-out is early embryonic lethal because of a defect in ventral morphogenesis, the in vivo function of this factor in heart development remains unresolved. To search for a requirement for Gata4 in heart development, we created mice harboring a single amino acid replacement in GATA-4 that impairs its physical interaction with its presumptive cardiac cofactor FOG-2. Gata4(ki/ki) mice die just after embryonic day (E) 12.5 exhibiting features in common with Fog2(-/-) embryos as well as additional semilunar cardiac valve defects and a double-outlet right ventricle. These findings establish an intrinsic requirement for GATA-4 in heart development. We also infer that GATA-4 function is dependent on interaction with FOG-2 and, very likely, an additional FOG protein for distinct aspects of heart formation.
Crispino
J D
JD
Division of Hematology and Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
Lodish
M B
MB
Thurberg
B L
BL
Litovsky
S H
SH
Collins
T
T
Molkentin
J D
JD
Orkin
S H
SH
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D003330:Coronary Vessel Anomalies / Q000196:embryology / Q000235:genetics*; D003331:Coronary Vessels / Q000196:embryology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000235:genetics; D050981:Erythroid-Specific DNA-Binding Factors; D005318:Fetal Heart / Q000254:growth & development* / Q000473:pathology; D050991:GATA4 Transcription Factor; D005804:Genes, Lethal; D005865:Gestational Age; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D014157:Transcription Factors / Q000096:biosynthesis / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014633:Valine / Q000737:chemistry; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050991:GATA4 Transcription Factor; D014157:Transcription Factors; D014633:Valine; D029961:Zebrafish Proteins; C095572:Hand1 protein, mouse; C498766:Hand2 protein, mouse; C492170:Zfpm2 protein, mouse; C410915:hand2 protein, zebrafish; C097341:helix-loop-helix protein, eHAND