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The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis

Nature Genetics volume 18, pages 271–275 (1998)Cite this article

Abstract

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 Thingl, encodes a basic helix-loop-helix (bHLH) transcription factor that starts to be expressed during pre-implantation development. After implantation, Handl expression is restricted to placental trophoblast cells and later to embryonic cardiac and neural crest cells1–3. 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, Handl is essential for differentiation of both trophoblast and cardiomyocytes, which are embryologically distinct cell lineages.

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References

  1. Cross, J.C. et al. Hxt encodes a basic helix-loop-helix transcription factor that regulates trophoblast cell development. Development 121, 2513–2523 (1995).

    CAS  PubMed  Google Scholar 

  2. Cserjesi, P., Brown, D., Lyons, G.E. & Olson, E.N. Expression of the novel basic helix-loop-helix gene eHAND in neural crest derivatives and extraembryonic membranes during mouse development. Dev. Biol. 170, 664–678 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Hollenberg, S.M., Sternglanz, R., Cheng, P.F. & Weintraub, H. Identification of a new family of tissue-specific basic helix-loop-helix proteins with a two-hybrid system. Mol. Cell. Biol. 15, 3813–3822 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Srivastava, D., Cserjesi, P. & Olson, E.N. A subclass of bHLH proteins required for cardiac morphogenesis. Science 270, 1995–1999 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Cross, J.C., Werb, Z. & Fisher, S.J. Implantation and the placenta: key pieces of the development puzzle. Science 266, 1508–1518 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Copp, A.J. Death before birth: clues from gene knockouts and mutations. Trends Genet. 11, 87–93 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Knudsen, T.B., Blackburn, M.R., Chinsky, J.M., Airhart, M.J. & Kellems, R.E. Ontogeny of adenosine deaminase in the mouse decidua and placenta: immunolocalization and embryo transfer studies. Biol. Reprod. 44, 171–184 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Alexander, C.M. et al. Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation. Development 122, 1723–1736 (1996).

    CAS  PubMed  Google Scholar 

  9. Nieto, M.A., Bennett, M.F., Sargent, M.G. & Wilkinson, D.G. Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene. Development 116, 227–237 (1992).

    CAS  PubMed  Google Scholar 

  10. Smith, D.E., Del Amo, F.F. & Gridley, T. Isolation of Sna, a mouse gene homologous to the Drosophila genes snail and escargot: its expression pattern suggests multiple roles during postimplantation development. Development 116, 1033–1039 (1992).

    CAS  PubMed  Google Scholar 

  11. Guillemot, F., Nagy, A., Auerbach, A., Rossant, J. & Joyner, A.L. Essential role of Mash-2 in extraembryonic development. Nature 371, 333–336 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Lescisin, K., Varmuza, S. & Rossant, J. Isolation and characterization of a novel trophoblast-specif ic cDNA in the mouse. Genes Dev. 2, 1639–1646 (1988).

    Article  CAS  PubMed  Google Scholar 

  13. Jackson, L.L., Colosi, P., Talamantes, F. & Linzer, D.I. Molecular cloning of mouse placental lactogen cDNA. Proc. Natl. Acad. Sci. USA 83, 8496–8500 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cheng, A.K. & Robertson, E.J. The murine LIM-kinase gene (limk) encodes a novel serine threonine kinase expressed predominantly in trophoblast giant cells and the developing nervous system. Mech. Dev. 52, 187–197 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Ilgren, E.B. Control of trophoblastic growth. Placenta 4, 307–328 (1983).

    Article  CAS  PubMed  Google Scholar 

  16. Olson, E.N. & Srivastava, D. Molecular pathways controlling heart development. Science 272, 671–676 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Nagy, A. & Rossant, J. Production of completely ES cell-derived fetuses, in Gene targeting: A practical Approach (ed. Joyner, A.) 147–179 (Oxford University Press, Oxford, 1993).

    Google Scholar 

  18. Friedrich, G. & Soriano, P. Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice. Genes Dev. 5, 1513–1523 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Srivastava, D. et al. Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nature Genet. 16, 154–160 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Lyons, I. et al. Myogenic and morphogenic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev. 9, 1654–1666 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Biben, C. & Harvey, R.P. Homeodomain factor Nkx2-5 controls left/right asymmetric expression of bHLH gene eHand during murine heart development. Genes Dev. 11, 1357–1369 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Shalaby, F. et a1. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Wurst, W. & Joyner, A. Production of targeted embryonic stem cell clones. in Gene Targeting: A Practical Approach (ed. Joyner, A.) 33–61 (Oxford University Press, Oxford, 1993).

    Google Scholar 

  24. Hogan, B., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo : A Laboratory Manual, (Cold Spring Harbor Laboratory, Cold Spring Harbor, 1986).

  25. Millen, K. & Hui, C. Radioactive hybridization of tissue sections, in A Laboratory Guide to RNA: Isolation, Analysis and Synthesis (ed. Krieg, P.) 339–355 (Wiley-Liss, New York, 1996).

  26. Lee, M.H., Reynisdottir, I. & Massague, J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 9, 639–649 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Kubalak, S.W., Miller-Hance, W.C., O'Brien, T.X., Dyson, E. & Chien, K.R. Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis. J. Biol. Chem. 269, 16961–16970 (1994).

    CAS  PubMed  Google Scholar 

  28. Sassoon, D.A., Garner, I. & Buckingham, M. Transcripts of alpha-cardiac and alpha-skeletal actins are early markers for myogenesis in the mouse embryo. Development 104, 155–164 (1988).

    CAS  PubMed  Google Scholar 

  29. Lints, T.J., Parsons, L.M., Hartley, L., Lyons, I. & Harvey, R.P. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 119, 419–431 (1993).

    CAS  PubMed  Google Scholar 

  30. Arceci, R.J., King, A.A.J., Simon, M.C., Orkin, S.H. & Wilson, D.B. Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart. Mol. Cell. Biol. 13, 2235–2246 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Edmondson, D.G., Lyons, G.E., Martin, J.F. & Olson, E.N. Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis. Development 120, 1251–1263 (1994).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Program in Development and Fetal Health, Samuel Launenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada

    Pual Riley, Lynn Anaon-Cartwight & James C. Cross

  2. Departments of Molecular and Medical Genetics,

    James C. Cross

  3. Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, M5G 1X5, Canada

    James C. Cross

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  1. Pual Riley
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  2. Lynn Anaon-Cartwight
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  3. James C. Cross
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Correspondence to James C. Cross.

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Riley, P., Anaon-Cartwight, L. & Cross, J. The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis. Nat Genet 18, 271–275 (1998). https://doi.org/10.1038/ng0398-271

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