The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis.
The placenta and cardiovascular system are the first organ systems to form during mammalian embryogenesis. We show here that a single gene is critical for development of both. The Hand1 gene, previously called Hxt, eHAND and Thing1, encodes a basic helix-loop-helix (bHLH) transcription factor that starts to be expressed during pre-implantation development. After implantation, Hand1 expression is restricted to placental trophoblast cells and later to embryonic cardiac and neural crest cells. We generated Hand1-null mutant mice by gene targetting. Homozygous mutant embryos arrested by embryonic day (E) 7.5 of gestation with defects in trophoblast giant cell differentiation. This early mortality could be rescued by aggregation of mutant embryos with wild-type tetraploid embryos, which contribute wild-type cells to the trophoblast, but not the embryo. By E10.5, however, the Hand1-null fetuses derived from tetraploid chimaeras died due to cardiac failure. Their heart tubes showed abnormal looping and ventricular myocardial differentiation. Therefore, Hand1 is essential for differentiation of both trophoblast and cardiomyocytes, which are embryologically distinct cell lineages.
Riley
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Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Anson-Cartwright
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Cross
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JC
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D010064:Embryo Implantation; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005260:Female; D005313:Fetal Death / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D015726:Giant Cells; D006321:Heart / Q000196:embryology*; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D020409:Molecular Motor Proteins; D009206:Myocardium / Q000473:pathology*; D010920:Placenta / Q000473:pathology / Q000502:physiology*; D011247:Pregnancy; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014327:Trophoblasts / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D005819:Genetic Markers; D008869:Microtubule-Associated Proteins; D020409:Molecular Motor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C489311:Ascl2 protein, mouse; C095572:Hand1 protein, mouse; C075341:KIP2 protein, S cerevisiae; C097341:helix-loop-helix protein, eHAND