Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1997 Jul 16;16(14):4393–4402. doi: 10.1093/emboj/16.14.4393

Deletion of a HoxD enhancer induces transcriptional heterochrony leading to transposition of the sacrum.

J Zákány 1, M Gérard 1, B Favier 1, D Duboule 1
PMCID: PMC1170065  PMID: 9250683

Abstract

A phylogenetically conserved transcriptional enhancer necessary for the activation of Hoxd-11 was deleted from the HoxD complex of mice by targeted mutagenesis. While genetic and expression analyses demonstrated the role of this regulatory element in the activation of Hoxd-11 during early somitogenesis, the function of this gene in developing limbs and the urogenital system was not affected, suggesting that Hox transcriptional controls are different in different axial structures. In the trunk of mutant embryos, transcriptional activation of Hoxd-11 and Hoxd-10 was severely delayed, but subsequently resumed with appropriate spatial distributions. The resulting caudal transposition of the sacrum indicates that proper vertebral specification requires a precise temporal control of Hox gene expression, in addition to spatial regulation. A slight time delay in expression (transcriptional heterochrony) cannot be compensated for at a later developmental stage, eventually leading to morphological alterations.

Full Text

The Full Text of this article is available as a PDF (563.2 KB).

Selected References

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

  1. Alkema M. J., Bronk M., Verhoeven E., Otte A., van 't Veer L. J., Berns A., van Lohuizen M. Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex. Genes Dev. 1997 Jan 15;11(2):226–240. doi: 10.1101/gad.11.2.226. [DOI] [PubMed] [Google Scholar]
  2. Alkema M. J., van der Lugt N. M., Bobeldijk R. C., Berns A., van Lohuizen M. Transformation of axial skeleton due to overexpression of bmi-1 in transgenic mice. Nature. 1995 Apr 20;374(6524):724–727. doi: 10.1038/374724a0. [DOI] [PubMed] [Google Scholar]
  3. Burke A. C., Nelson C. E., Morgan B. A., Tabin C. Hox genes and the evolution of vertebrate axial morphology. Development. 1995 Feb;121(2):333–346. doi: 10.1242/dev.121.2.333. [DOI] [PubMed] [Google Scholar]
  4. Carroll S. B. Homeotic genes and the evolution of arthropods and chordates. Nature. 1995 Aug 10;376(6540):479–485. doi: 10.1038/376479a0. [DOI] [PubMed] [Google Scholar]
  5. Castelli-Gair J., Akam M. How the Hox gene Ultrabithorax specifies two different segments: the significance of spatial and temporal regulation within metameres. Development. 1995 Sep;121(9):2973–2982. doi: 10.1242/dev.121.9.2973. [DOI] [PubMed] [Google Scholar]
  6. Coates M. I. The origin of vertebrate limbs. Dev Suppl. 1994:169–180. [PubMed] [Google Scholar]
  7. Davis A. P., Capecchi M. R. A mutational analysis of the 5' HoxD genes: dissection of genetic interactions during limb development in the mouse. Development. 1996 Apr;122(4):1175–1185. doi: 10.1242/dev.122.4.1175. [DOI] [PubMed] [Google Scholar]
  8. Davis A. P., Capecchi M. R. Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of hoxd-11. Development. 1994 Aug;120(8):2187–2198. doi: 10.1242/dev.120.8.2187. [DOI] [PubMed] [Google Scholar]
  9. Dollé P., Duboule D. Two gene members of the murine HOX-5 complex show regional and cell-type specific expression in developing limbs and gonads. EMBO J. 1989 May;8(5):1507–1515. doi: 10.1002/j.1460-2075.1989.tb03535.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dollé P., Izpisúa-Belmonte J. C., Falkenstein H., Renucci A., Duboule D. Coordinate expression of the murine Hox-5 complex homoeobox-containing genes during limb pattern formation. Nature. 1989 Dec 14;342(6251):767–772. doi: 10.1038/342767a0. [DOI] [PubMed] [Google Scholar]
  11. Dupé V., Davenne M., Brocard J., Dollé P., Mark M., Dierich A., Chambon P., Rijli F. M. In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE). Development. 1997 Jan;124(2):399–410. doi: 10.1242/dev.124.2.399. [DOI] [PubMed] [Google Scholar]
  12. Favier B., Le Meur M., Chambon P., Dollé P. Axial skeleton homeosis and forelimb malformations in Hoxd-11 mutant mice. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):310–314. doi: 10.1073/pnas.92.1.310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fromental-Ramain C., Warot X., Lakkaraju S., Favier B., Haack H., Birling C., Dierich A., Doll e P., Chambon P. Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning. Development. 1996 Feb;122(2):461–472. doi: 10.1242/dev.122.2.461. [DOI] [PubMed] [Google Scholar]
  14. Gaunt S. J. Conservation in the Hox code during morphological evolution. Int J Dev Biol. 1994 Sep;38(3):549–552. [PubMed] [Google Scholar]
  15. Gould A., Morrison A., Sproat G., White R. A., Krumlauf R. Positive cross-regulation and enhancer sharing: two mechanisms for specifying overlapping Hox expression patterns. Genes Dev. 1997 Apr 1;11(7):900–913. doi: 10.1101/gad.11.7.900. [DOI] [PubMed] [Google Scholar]
  16. Gérard M., Chen J. Y., Gronemeyer H., Chambon P., Duboule D., Zákány J. In vivo targeted mutagenesis of a regulatory element required for positioning the Hoxd-11 and Hoxd-10 expression boundaries. Genes Dev. 1996 Sep 15;10(18):2326–2334. doi: 10.1101/gad.10.18.2326. [DOI] [PubMed] [Google Scholar]
  17. Gérard M., Duboule D., Zákány J. Structure and activity of regulatory elements involved in the activation of the Hoxd-11 gene during late gastrulation. EMBO J. 1993 Sep;12(9):3539–3550. doi: 10.1002/j.1460-2075.1993.tb06028.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hérault Y., Hraba-Renevey S., van der Hoeven F., Duboule D. Function of the Evx-2 gene in the morphogenesis of vertebrate limbs. EMBO J. 1996 Dec 2;15(23):6727–6738. [PMC free article] [PubMed] [Google Scholar]
  19. Izpisúa-Belmonte J. C., Falkenstein H., Dollé P., Renucci A., Duboule D. Murine genes related to the Drosophila AbdB homeotic genes are sequentially expressed during development of the posterior part of the body. EMBO J. 1991 Aug;10(8):2279–2289. doi: 10.1002/j.1460-2075.1991.tb07764.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Krumlauf R. Hox genes in vertebrate development. Cell. 1994 Jul 29;78(2):191–201. doi: 10.1016/0092-8674(94)90290-9. [DOI] [PubMed] [Google Scholar]
  21. Rijli F. M., Dollé P., Fraulob V., LeMeur M., Chambon P. Insertion of a targeting construct in a Hoxd-10 allele can influence the control of Hoxd-9 expression. Dev Dyn. 1994 Dec;201(4):366–377. doi: 10.1002/aja.1002010408. [DOI] [PubMed] [Google Scholar]
  22. Shashikant C. S., Ruddle F. H. Combinations of closely situated cis-acting elements determine tissue-specific patterns and anterior extent of early Hoxc8 expression. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12364–12369. doi: 10.1073/pnas.93.22.12364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Studer M., Lumsden A., Ariza-McNaughton L., Bradley A., Krumlauf R. Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature. 1996 Dec 19;384(6610):630–634. doi: 10.1038/384630a0. [DOI] [PubMed] [Google Scholar]
  24. Subramanian V., Meyer B. I., Gruss P. Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes. Cell. 1995 Nov 17;83(4):641–653. doi: 10.1016/0092-8674(95)90104-3. [DOI] [PubMed] [Google Scholar]
  25. Vogels R., Charité J., de Graaff W., Deschamps J. Proximal cis-acting elements cooperate to set Hoxb-7 (Hox-2.3) expression boundaries in transgenic mice. Development. 1993 May;118(1):71–82. doi: 10.1242/dev.118.1.71. [DOI] [PubMed] [Google Scholar]
  26. Walters M. C., Magis W., Fiering S., Eidemiller J., Scalzo D., Groudine M., Martin D. I. Transcriptional enhancers act in cis to suppress position-effect variegation. Genes Dev. 1996 Jan 15;10(2):185–195. doi: 10.1101/gad.10.2.185. [DOI] [PubMed] [Google Scholar]
  27. Whiting J., Marshall H., Cook M., Krumlauf R., Rigby P. W., Stott D., Allemann R. K. Multiple spatially specific enhancers are required to reconstruct the pattern of Hox-2.6 gene expression. Genes Dev. 1991 Nov;5(11):2048–2059. doi: 10.1101/gad.5.11.2048. [DOI] [PubMed] [Google Scholar]
  28. Yu B. D., Hess J. L., Horning S. E., Brown G. A., Korsmeyer S. J. Altered Hox expression and segmental identity in Mll-mutant mice. Nature. 1995 Nov 30;378(6556):505–508. doi: 10.1038/378505a0. [DOI] [PubMed] [Google Scholar]
  29. Zappavigna V., Renucci A., Izpisúa-Belmonte J. C., Urier G., Peschle C., Duboule D. HOX4 genes encode transcription factors with potential auto- and cross-regulatory capacities. EMBO J. 1991 Dec;10(13):4177–4187. doi: 10.1002/j.1460-2075.1991.tb04996.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Zákány J., Duboule D. Synpolydactyly in mice with a targeted deficiency in the HoxD complex. Nature. 1996 Nov 7;384(6604):69–71. doi: 10.1038/384069a0. [DOI] [PubMed] [Google Scholar]
  31. Zákány J., Gérard M., Favier B., Potter S. S., Duboule D. Functional equivalence and rescue among group 11 Hox gene products in vertebral patterning. Dev Biol. 1996 Jun 15;176(2):325–328. doi: 10.1006/dbio.1996.0137. [DOI] [PubMed] [Google Scholar]
  32. van der Hoeven F., Zákány J., Duboule D. Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls. Cell. 1996 Jun 28;85(7):1025–1035. doi: 10.1016/s0092-8674(00)81303-3. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES