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:

RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex

Nature Genetics volume 22, pages 394–399 (1999)Cite this article

Abstract

LIM domains1 are required for both inhibitory effects on LIM homeodomain transcription factors and synergistic transcriptional activation events1,2,3,4. The inhibitory actions of the LIM domain can often be overcome by the LIM co-regulator known as CLIM2, LDB1 and NLI (referred to hereafter as CLIM2; refs 2, 3, 4). The association of the CLIM cofactors with LIM domains does not, however, improve the DNA-binding ability of LIM homeodomain proteins4,5, suggesting the action of a LIM-associated inhibitor factor. Here we present evidence that LIM domains are capable of binding a novel RING-H2 zinc-finger protein, Rlim (for RING finger LIM domain-binding protein), which acts as a negative co-regulator via the recruitment of the Sin3A/histone deacetylase corepressor complex. A corepressor function of RLIM is also suggested by in vivo studies of chick wing development. Overexpression of the gene Rnf12, encoding Rlim, results in phenotypes similar to those observed after inhibition of the LIM homeodomain factor LHX2, which is required for the formation of distal structures along the proximodistal axis, or by overexpression of dominant-negative CLIM1. We conclude that Rlim is a novel corepressor that recruits histone deacetylase-containing complexes to the LIM domain.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Rlim, a novel LIM domain-binding RING zinc-finger protein.
Figure 2: Comparison of Rnf12 (encoding Rlim), Ldb2 (encoding Clim1) and Ldb1 (encoding Clim2) expression patterns during mouse embryogenesis by in situ hybridizations on serial sections at E7.5 (a) and E15.5 (b–g).
Figure 3: Rlim repressor function.
Figure 4: RNF12 regulates chick limb development.
Figure 5: Overexpression of dominant-negative CLIM1 or LHX2 perturbs limb outgrowth.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Dawid, I.B., Breen, J.J. & Toyama, R. LIM domains: multiple roles as adaptors and functional modifiers in protein interactions. Trends Genet. 14 , 156–162 (1998).

    Article  CAS  Google Scholar 

  2. Taira, M., Otani, H., Saint-Jeannet, J.-P. & Dawid, I.B. Role of the LIM class homeodomain protein Xlim-1 in neural and muscle induction by the Spemann organizer in Xenopus. Nature 372, 677–679 (1994).

    Article  CAS  Google Scholar 

  3. Agulnick, A.D. et al. Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature 384, 270– 272 (1996).

    Article  CAS  Google Scholar 

  4. Bach, I., Carrière, C., Ostendorff, H.P., Andersen, B. & Rosenfeld, M.G. A family of LIM domain interacting cofactors confer transcriptional synergism between LIM and Otx homeoproteins. Genes Dev. 11, 1370–1380 (1997).

    Article  CAS  Google Scholar 

  5. Jurata, L.W. & Gill, G.N. Functional analysis of the nuclear LIM domain interactor NLI. Mol. Cell. Biol. 17, 5688–5698 (1997).

    Article  CAS  Google Scholar 

  6. Freemont, P.S. The RING finger. A novel protein sequence motif related to the zinc finger. Ann. N. Y. Acad. Sci. 684, 174– 192 (1993).

    Article  CAS  Google Scholar 

  7. Tranque, P., Crossin, K.L., Cirelli, C., Edelman, G.M. & Mauro, V.P. Identification and characterization of a RING zinc finger gene (C-RZF) expressed in chicken embryo cells. Proc. Natl Acad. Sci. USA 93, 3105– 3109 (1996).

    Article  CAS  Google Scholar 

  8. Jurata, L.W., Kenny, D.A. & Gill, G.N. Nuclear LIM interactor, a rhombotin and LIM homeodomain interacting protein, is expressed early in neuronal development. Proc. Natl Acad. Sci. USA 93, 11693– 11698 (1996).

    Article  CAS  Google Scholar 

  9. Toyama, R., Kobayashi, M., Tomita, T. & Dawid, I.B. Expression of LIM-domain binding protein (ldb) genes during zebrafish embryogenesis. Mech. Dev. 71, 197–200 (1998).

    Article  CAS  Google Scholar 

  10. Bach, I. et al. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc. Natl Acad. Sci. USA 92, 2720–2724 (1995).

    Article  CAS  Google Scholar 

  11. Schoorlemmer J. et al. Ring 1A is a transcriptional repressor that interacts with the polycomb-M33 protein and is expressed at rhombomere boundaries in the mouse hindbrain. EMBO J. 19, 5930– 5942 (1997).

    Article  Google Scholar 

  12. Moosmann, P., Georgiev, O., Le Douarin, B., Bourquin, J.P. & Schaffner W. Transcriptional repression by RING finger protein TIF β that interacts with the KRAB repressor domain of KOX1. Nucleic Acids Res. 24, 4859–4867 (1996).

    Article  CAS  Google Scholar 

  13. Torchia, J., Glass, C.K. & Rosenfeld, M.G. Co-activators and co-repressors in the integration of transcriptional responses. Curr. Opin. Cell Biol. 10, 373–383 (1998).

    Article  CAS  Google Scholar 

  14. Heinzel, T. et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387, 43–48 (1997).

    Article  CAS  Google Scholar 

  15. Laherty, C.D. et al. SAP30, a component of the mSin3 corepressor complex involved in N-CoR-mediated repression by specific transcription factors. Mol. Cell 2, 33–42 ( 1998).

    Article  CAS  Google Scholar 

  16. Nagy, L. et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89, 373–380 (1997).

    Article  CAS  Google Scholar 

  17. Vogel, A., Rodriguez, C., Warnken, W. & Izpisúa Belmonte, J.C. Dorsal cell fate specified by chick Lmx1 during vertebrate limb development. Nature 378, 716– 720 (1995).

    Article  CAS  Google Scholar 

  18. Riddle, R. et al. Induction of the LIM homeobox gene Lmx-1 by Wnt7a establishes dorsoventral pattern in the vertebrate limb. Cell 83 , 631–640 (1995).

    Article  CAS  Google Scholar 

  19. Rodriguez-Esteban, C. et al. Lhx2, a vertebrate homologue of apterous, regulates vertebrate limb outgrowth. Development 125, 3925–3934 (1998).

    CAS  PubMed  Google Scholar 

  20. Mahmood, R. et al. A role for FGF8 in the initiation and maintenance of vertebrate limb bud outgrowth. Curr. Biol. 5, 797– 806 (1995).

    Article  CAS  Google Scholar 

  21. Crossley, P.H., Minowada, G., MacArthur, C.A. & Martin, G.R. Roles for FGF-8 in the induction, initiation and maintenance of chick limb development. Cell 84, 127– 136 (1996).

    Article  CAS  Google Scholar 

  22. Vogel, A., Rodriguez, C. & Izpisúa Belmonte, J.C. Involvement of FGF-8 in initiation, outgrowth and patterning of the vertebrate limb. Development 122, 1737–1750 (1996).

    CAS  PubMed  Google Scholar 

  23. Laufer, E., Nelson, C.E., Johnson, R.L., Morgan, B.A. & Tabin, C. Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 79, 993 –1003 (1994).

    Article  CAS  Google Scholar 

  24. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407– 413 (1996).

    Article  CAS  Google Scholar 

  25. Breen, J.J., Agulnick, A.D., Westphal, H. & Dawid, I. Interactions between LIM domains and the LIM domain-binding protein Ldb1. J. Biol. Chem. 273, 4712– 4717 (1998).

    Article  CAS  Google Scholar 

  26. Morcillo, P., Rosen, C., Baylies, M.K. & Dorsett, D. Chip, a widely expressed chromosomal protein required for segmentation and activity of a remote wing margin enhancer in Drosophila. Genes Dev. 11, 2729–2740 (1997).

    Article  CAS  Google Scholar 

  27. Niswander, L., Tickle, C., Vogel, A., Booth, I. & Martin, G.R. FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb. Cell 75, 579–587 (1993).

    Article  CAS  Google Scholar 

  28. Morgan, B.A., Izpisúa Belmonte, J.C., Duboule, D. & Tabin, C.J. Targeted misexpression of Hox-4.6 in the avian limb bud causes apparent homeotic transformations. Nature 358, 236– 239 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Kintner for initial X. laevis mRNA injections; O. Bernard for the Kiz-1 expression plasmid; C. Nelson for cell culture; P. Meyers for assistance in figure preparation; M. Fisher for assistance in manuscript preparation; E. De Robertis, E. Osmundson, M. Ruchhoef, S. O'Connell, M. Wegner and R. Stan for providing reagents and advice; and A. Ryan and H. Ostendorff for comments on the manuscript. C.C. was a fellow of the LALOR Foundation. This work is supported by NIH grants to B.A. (AR044882 and AR02080), J.C.I.B. and M.G.R.; by the Irving Weinstein Foundation to B.A.; and by a G. Harold and L.Y. Mathers Charitable Foundation grant to J.C.I.B.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, Eukaryotic Regulatory Biology Program, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, 92093-0648, California, USA

    Ingolf Bach, Catherine Carrière, Anna Krones & Michael G. Rosenfeld

  2. Gene Expression Laboratory, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, 92186, California, USA

    Concepción Rodriguez-Esteban & Juan Carlos Izpisúa Belmonte

  3. The Clayton Foundation, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla , 92186, California, USA

    Anil Bhushan

  4. Whittier Diabetes Program, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, 92093-0648, California, USA

    David W. Rose

  5. Division of Endocrinology and Metabolism, University of California, San Diego, School of Medicine, 9500 Gilman Drive , La Jolla, 92093-0648, California, USA

    David W. Rose & Bogi Andersen

  6. Division of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive , La Jolla, 92093-0648, California, USA

    Christopher K. Glass

  7. Center for Molecular Neurobiology, University of Hamburg , Martinistr. 85, Hamburg, 20246, Germany

    Ingolf Bach

Authors
  1. Ingolf Bach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Concepción Rodriguez-Esteban
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catherine Carrière
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anil Bhushan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna Krones
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David W. Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christopher K. Glass
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bogi Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Juan Carlos Izpisúa Belmonte
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael G. Rosenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ingolf Bach, Juan Carlos Izpisúa Belmonte or Michael G. Rosenfeld.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bach, I., Rodriguez-Esteban, C., Carrière, C. et al. RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nat Genet 22, 394–399 (1999). https://doi.org/10.1038/11970

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/11970

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