Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Sep 3;93(18):9636–9640. doi: 10.1073/pnas.93.18.9636

Functional specificity of Hoxa-4 in vertebral patterning lies outside of the homeodomain.

T L Sreenath 1, R A Pollock 1, C J Bieberich 1
PMCID: PMC38480  PMID: 8790382

Abstract

The Hox family of proteins plays a central role in establishing the body plan of a wide range of metazoan organisms. Each member of this family of transcriptional regulators has a distinct functional specificity, yet they bind to similar DNA target sequences through their conserved homeodomain. The mechanisms whereby Hox proteins achieve their diverse specificities in vivo remain undefined. Using the opposing effects of Hoxa-4 and Hoxc-8 in vertebral patterning, we demonstrate by replacing the homeodomain of Hoxa-4 with that of Hoxc-8 that the functional specificity of Hoxa-4 does not track with the homeodomain. These observations provide evidence that other regions of Hox proteins play an important role in mediating functional specificity during mammalian embryogenesis.

Full text

PDF
9636

Images in this article

9637Fig. 1
on p.9637
9638Fig. 2
on p.9638

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Awgulewitsch A., Jacobs D. Differential expression of Hox 3.1 protein in subregions of the embryonic and adult spinal cord. Development. 1990 Mar;108(3):411–420. doi: 10.1242/dev.108.3.411. [DOI] [PubMed] [Google Scholar]
  2. Beachy P. A., Varkey J., Young K. E., von Kessler D. P., Sun B. I., Ekker S. C. Cooperative binding of an Ultrabithorax homeodomain protein to nearby and distant DNA sites. Mol Cell Biol. 1993 Nov;13(11):6941–6956. doi: 10.1128/mcb.13.11.6941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Behringer R. R., Crotty D. A., Tennyson V. M., Brinster R. L., Palmiter R. D., Wolgemuth D. J. Sequences 5' of the homeobox of the Hox-1.4 gene direct tissue-specific expression of lacZ during mouse development. Development. 1993 Mar;117(3):823–833. doi: 10.1242/dev.117.3.823. [DOI] [PubMed] [Google Scholar]
  4. Bradshaw M. S., Shashikant C. S., Belting H. G., Bollekens J. A., Ruddle F. H. A long-range regulatory element of Hoxc8 identified by using the pClasper vector. Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2426–2430. doi: 10.1073/pnas.93.6.2426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chan S. K., Jaffe L., Capovilla M., Botas J., Mann R. S. The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein. Cell. 1994 Aug 26;78(4):603–615. doi: 10.1016/0092-8674(94)90525-8. [DOI] [PubMed] [Google Scholar]
  6. Chan S. K., Mann R. S. The segment identity functions of Ultrabithorax are contained within its homeo domain and carboxy-terminal sequences. Genes Dev. 1993 May;7(5):796–811. doi: 10.1101/gad.7.5.796. [DOI] [PubMed] [Google Scholar]
  7. Chang C. P., Shen W. F., Rozenfeld S., Lawrence H. J., Largman C., Cleary M. L. Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins. Genes Dev. 1995 Mar 15;9(6):663–674. doi: 10.1101/gad.9.6.663. [DOI] [PubMed] [Google Scholar]
  8. Condie B. G., Capecchi M. R. Mice with targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 reveal synergistic interactions. Nature. 1994 Jul 28;370(6487):304–307. doi: 10.1038/370304a0. [DOI] [PubMed] [Google Scholar]
  9. Copeland J. W., Nasiadka A., Dietrich B. H., Krause H. M. Patterning of the Drosophila embryo by a homeodomain-deleted Ftz polypeptide. Nature. 1996 Jan 11;379(6561):162–165. doi: 10.1038/379162a0. [DOI] [PubMed] [Google Scholar]
  10. Desplan C., Theis J., O'Farrell P. H. The sequence specificity of homeodomain-DNA interaction. Cell. 1988 Sep 23;54(7):1081–1090. doi: 10.1016/0092-8674(88)90123-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ekker S. C., Young K. E., von Kessler D. P., Beachy P. A. Optimal DNA sequence recognition by the Ultrabithorax homeodomain of Drosophila. EMBO J. 1991 May;10(5):1179–1186. doi: 10.1002/j.1460-2075.1991.tb08058.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fitzpatrick V. D., Percival-Smith A., Ingles C. J., Krause H. M. Homeodomain-independent activity of the fushi tarazu polypeptide in Drosophila embryos. Nature. 1992 Apr 16;356(6370):610–612. doi: 10.1038/356610a0. [DOI] [PubMed] [Google Scholar]
  13. Florence B., Handrow R., Laughon A. DNA-binding specificity of the fushi tarazu homeodomain. Mol Cell Biol. 1991 Jul;11(7):3613–3623. doi: 10.1128/mcb.11.7.3613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Furukubo-Tokunaga K., Müller M., Affolter M., Pick L., Kloter U., Gehring W. J. In vivo analysis of the helix-turn-helix motif of the fushi tarazu homeo domain of Drosophila melanogaster. Genes Dev. 1992 Jun;6(6):1082–1096. doi: 10.1101/gad.6.6.1082. [DOI] [PubMed] [Google Scholar]
  15. Galliot B., Dollé P., Vigneron M., Featherstone M. S., Baron A., Duboule D. The mouse Hox-1.4 gene: primary structure, evidence for promoter activity and expression during development. Development. 1989 Oct;107(2):343–359. doi: 10.1242/dev.107.2.343. [DOI] [PubMed] [Google Scholar]
  16. Gehring W. J., Affolter M., Bürglin T. Homeodomain proteins. Annu Rev Biochem. 1994;63:487–526. doi: 10.1146/annurev.bi.63.070194.002415. [DOI] [PubMed] [Google Scholar]
  17. Gibson G., Schier A., LeMotte P., Gehring W. J. The specificities of Sex combs reduced and Antennapedia are defined by a distinct portion of each protein that includes the homeodomain. Cell. 1990 Sep 21;62(6):1087–1103. doi: 10.1016/0092-8674(90)90386-s. [DOI] [PubMed] [Google Scholar]
  18. Hayashi S., Scott M. P. What determines the specificity of action of Drosophila homeodomain proteins? Cell. 1990 Nov 30;63(5):883–894. doi: 10.1016/0092-8674(90)90492-w. [DOI] [PubMed] [Google Scholar]
  19. Hoey T., Levine M. Divergent homeo box proteins recognize similar DNA sequences in Drosophila. Nature. 1988 Apr 28;332(6167):858–861. doi: 10.1038/332858a0. [DOI] [PubMed] [Google Scholar]
  20. Horan G. S., Kovàcs E. N., Behringer R. R., Featherstone M. S. Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: evidence for unique and redundant function. Dev Biol. 1995 May;169(1):359–372. doi: 10.1006/dbio.1995.1150. [DOI] [PubMed] [Google Scholar]
  21. Horan G. S., Wu K., Wolgemuth D. J., Behringer R. R. Homeotic transformation of cervical vertebrae in Hoxa-4 mutant mice. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12644–12648. doi: 10.1073/pnas.91.26.12644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Johnson F. B., Parker E., Krasnow M. A. Extradenticle protein is a selective cofactor for the Drosophila homeotics: role of the homeodomain and YPWM amino acid motif in the interaction. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):739–743. doi: 10.1073/pnas.92.3.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Knittel T., Kessel M., Kim M. H., Gruss P. A conserved enhancer of the human and murine Hoxa-7 gene specifies the anterior boundary of expression during embryonal development. Development. 1995 Apr;121(4):1077–1088. doi: 10.1242/dev.121.4.1077. [DOI] [PubMed] [Google Scholar]
  24. Kuziora M. A., McGinnis W. A homeodomain substitution changes the regulatory specificity of the deformed protein in Drosophila embryos. Cell. 1989 Nov 3;59(3):563–571. doi: 10.1016/0092-8674(89)90039-1. [DOI] [PubMed] [Google Scholar]
  25. Lawrence P. A., Morata G. Homeobox genes: their function in Drosophila segmentation and pattern formation. Cell. 1994 Jul 29;78(2):181–189. doi: 10.1016/0092-8674(94)90289-5. [DOI] [PubMed] [Google Scholar]
  26. Le Mouellic H., Lallemand Y., Brûlet P. Homeosis in the mouse induced by a null mutation in the Hox-3.1 gene. Cell. 1992 Apr 17;69(2):251–264. doi: 10.1016/0092-8674(92)90406-3. [DOI] [PubMed] [Google Scholar]
  27. Lin L., McGinnis W. Mapping functional specificity in the Dfd and Ubx homeo domains. Genes Dev. 1992 Jun;6(6):1071–1081. doi: 10.1101/gad.6.6.1071. [DOI] [PubMed] [Google Scholar]
  28. McGinnis W., Krumlauf R. Homeobox genes and axial patterning. Cell. 1992 Jan 24;68(2):283–302. doi: 10.1016/0092-8674(92)90471-n. [DOI] [PubMed] [Google Scholar]
  29. Otting G., Qian Y. Q., Billeter M., Müller M., Affolter M., Gehring W. J., Wüthrich K. Protein--DNA contacts in the structure of a homeodomain--DNA complex determined by nuclear magnetic resonance spectroscopy in solution. EMBO J. 1990 Oct;9(10):3085–3092. doi: 10.1002/j.1460-2075.1990.tb07505.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Phelan M. L., Rambaldi I., Featherstone M. S. Cooperative interactions between HOX and PBX proteins mediated by a conserved peptide motif. Mol Cell Biol. 1995 Aug;15(8):3989–3997. doi: 10.1128/mcb.15.8.3989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pollock R. A., Jay G., Bieberich C. J. Altering the boundaries of Hox3.1 expression: evidence for antipodal gene regulation. Cell. 1992 Dec 11;71(6):911–923. doi: 10.1016/0092-8674(92)90388-s. [DOI] [PubMed] [Google Scholar]
  32. Pollock R. A., Sreenath T., Ngo L., Bieberich C. J. Gain of function mutations for paralogous Hox genes: implications for the evolution of Hox gene function. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4492–4496. doi: 10.1073/pnas.92.10.4492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Püschel A. W., Balling R., Gruss P. Separate elements cause lineage restriction and specify boundaries of Hox-1.1 expression. Development. 1991 May;112(1):279–287. doi: 10.1242/dev.112.1.279. [DOI] [PubMed] [Google Scholar]
  34. Ruddle F. H., Bartels J. L., Bentley K. L., Kappen C., Murtha M. T., Pendleton J. W. Evolution of Hox genes. Annu Rev Genet. 1994;28:423–442. doi: 10.1146/annurev.ge.28.120194.002231. [DOI] [PubMed] [Google Scholar]
  35. Schubert F. R., Nieselt-Struwe K., Gruss P. The Antennapedia-type homeobox genes have evolved from three precursors separated early in metazoan evolution. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):143–147. doi: 10.1073/pnas.90.1.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shashikant C. S., Bieberich C. J., Belting H. G., Wang J. C., Borbély M. A., Ruddle F. H. Regulation of Hoxc-8 during mouse embryonic development: identification and characterization of critical elements involved in early neural tube expression. Development. 1995 Dec;121(12):4339–4347. doi: 10.1242/dev.121.12.4339. [DOI] [PubMed] [Google Scholar]
  37. Verbout A. J. The development of the vertebral column. Adv Anat Embryol Cell Biol. 1985;90:1–122. doi: 10.1007/978-3-642-69983-2. [DOI] [PubMed] [Google Scholar]
  38. Wilson D. S., Desplan C. Homeodomain proteins. Cooperating to be different. Curr Biol. 1995 Jan 1;5(1):32–34. doi: 10.1016/s0960-9822(95)00010-8. [DOI] [PubMed] [Google Scholar]
  39. Wolgemuth D. J., Behringer R. R., Mostoller M. P., Brinster R. L., Palmiter R. D. Transgenic mice overexpressing the mouse homoeobox-containing gene Hox-1.4 exhibit abnormal gut development. Nature. 1989 Feb 2;337(6206):464–467. doi: 10.1038/337464a0. [DOI] [PubMed] [Google Scholar]
  40. Zeng W., Andrew D. J., Mathies L. D., Horner M. A., Scott M. P. Ectopic expression and function of the Antp and Scr homeotic genes: the N terminus of the homeodomain is critical to functional specificity. Development. 1993 Jun;118(2):339–352. doi: 10.1242/dev.118.2.339. [DOI] [PubMed] [Google Scholar]
  41. van Dijk M. A., Murre C. extradenticle raises the DNA binding specificity of homeotic selector gene products. Cell. 1994 Aug 26;78(4):617–624. doi: 10.1016/0092-8674(94)90526-6. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES