Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Loss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development

Nature Genetics volume 26, pages 229–232 (2000)Cite this article

Abstract

Histone acetyltransferases regulate transcription, but little is known about the role of these enzymes in developmental processes. Gcn5 (encoded by Gcn5l2) and Pcaf, mouse histone acetyltransferases, share similar sequences and enzymatic activities1. Both interact with p300 and CBP (encoded by Ep300 and Crebbp, respectively), two other histone acetyltransferases that integrate multiple signalling pathways1. Pcaf is thought to participate in many of the cellular processes regulated by p300/CBP (refs 2–8), but the functions of Gcn5 are unknown in mammalian cells. Here we show that the gene Pcaf is dispensable in mice. In contrast, Gcn5l2-null embryos die during embryogenesis. These embryos develop normally to 7.5 days post coitum (d.p.c.), but their growth is severely retarded by 8.5 d.p.c. and they fail to form dorsal mesoderm lineages, including chordamesoderm and paraxial mesoderm. Differentiation of extra-embryonic and cardiac mesoderm seems to be unaffected. Loss of the dorsal mesoderm lineages is due to a high incidence of apoptosis in the Gcn5l2 mutants that begins before the onset of morphological abnormality. Embryos null for both Gcn5l2 and Pcaf show even more severe defects, indicating that these histone acetyltransferases have overlapping functions during embryogenesis. Our studies are the first to demonstrate that specific acetyltransferases are required for cell survival and mesoderm formation during mammalian development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Differential expression of Gcn5l2 and Pcaf in mouse embryos.
Figure 2: Disruption of Pcaf.
Figure 3: Gcn5l2-null mice die during embryogenesis.
Figure 4: Histologic and marker analyses of Gcn5l2-mutant embryos.
Figure 5: Apoptosis is increased in Gcn5l2-null embryos.
Figure 6: Mice null for both Pcaf and Gcn5l2 die around 7.5 d.p.c.

Similar content being viewed by others

References

  1. Xu, W., Edmondson, D.G. & Roth, S.Y. Mammalian GCN5 and P/CAF acetyltransferases have homologous amino-terminal domains important for recognition of nucleosomal substrates. Mol. Cell. Biol. 18, 5659–5669 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Blanco, J.C. et al. The histone acetylase PCAF is a nuclear receptor coactivator. Genes Dev. 12, 1638–1651 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu, L. et al. p53 sites acetylated in vitro by Pcaf and p300 are acetylated in vivo in response to DNA damage. Mol. Cell. Biol. 19, 1202–1209 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Puri, P.L. et al. Differential roles of p300 and PCAF acetyltransferases in muscle differentiation. Mol. Cell 1, 35–45 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Sakaguchi, K. et al. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 12, 2831–2841 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang, X.J., Ogryzko, V.V., Nishikawa, J., Howard, B.H. & Nakatani, Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382, 319–324 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Chakravarti, D. et al. A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity. Cell 96, 393–403 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Hamamori, Y. et al. Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A. Cell 96, 405–413 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Herrmann, B.G. & Kispert, A. The T genes in embryogenesis. Trends Genet. 10, 280–286 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Crossley, P.H. & Martin, G.R. The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development 121, 439–451 (1995).

    CAS  PubMed  Google Scholar 

  11. Burgess, R., Cserjesi, P., Ligon, K.L. & Olson, E.N. Paraxis: a basic helix-loop-helix protein expressed in paraxial mesoderm and developing somites. Dev. Biol. 168, 296–306 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Bettenhausen, B., Hrabe de Angelis, M., Simon, D., Guenet, J.L. & Gossler, A. Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila δ. Development 121, 2407–2418 (1995).

    CAS  PubMed  Google Scholar 

  13. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Sasaki, H. & Hogan, B.L. Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. Development 118, 47–59 (1993).

    CAS  PubMed  Google Scholar 

  15. Ang, S.L. & Rossant, J. Anterior mesendoderm induces mouse Engrailed genes in explant cultures. Development 118, 139–149 (1993).

    CAS  PubMed  Google Scholar 

  16. Wolf, C. et al. The M-twist gene of Mus is expressed in subsets of mesodermal cells and is closely related to the Xenopus X-twi and the Drosophila twist genes. Dev. Biol. 143, 363–373 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Ang, S.L. & Rossant, J. HNF-3 β is essential for node and notochord formation in mouse development. Cell 78, 561–574 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. Yao, T.P. et al. Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93, 361–372 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Hogan, B., Beddington, R., Costantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1994).

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the USARMC and the Robert A. Welch Foundation to S.Y.R. and a grant from the NIH to R.R.B.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Texas-M.D. Anderson Cancer Center, Houston, Texas, USA

    Wanting Xu, Diane G. Edmondson, Yvonne A. Evrard & Sharon Y. Roth

  2. Department of Molecular Genetics, University of Texas-M.D. Anderson Cancer Center, Houston, Texas, USA

    Maki Wakamiya & Richard R. Behringer

Authors
  1. Wanting Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diane G. Edmondson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yvonne A. Evrard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maki Wakamiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard R. Behringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sharon Y. Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sharon Y. Roth.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, W., Edmondson, D., Evrard, Y. et al. Loss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development. Nat Genet 26, 229–232 (2000). https://doi.org/10.1038/79973

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79973

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing