Development Genes and Evolution

, Volume 219, Issue 9–10, pp 481–496 | Cite as

Conservation of gene linkage in dispersed vertebrate NK homeobox clusters

  • Karl R. Wotton
  • Frida K. Weierud
  • José L. Juárez-Morales
  • Lúcia E. Alvares
  • Susanne Dietrich
  • Katharine E. Lewis
Original Article


Nk homeobox genes are important regulators of many different developmental processes including muscle, heart, central nervous system and sensory organ development. They are thought to have arisen as part of the ANTP megacluster, which also gave rise to Hox and ParaHox genes, and at least some NK genes remain tightly linked in all animals examined so far. The protostome–deuterostome ancestor probably contained a cluster of nine Nk genes: (Msx)–(Nk4/tinman)–(Nk3/bagpipe)–(Lbx/ladybird)–(Tlx/c15)–(Nk7)–(Nk6/hgtx)–(Nk1/slouch)–(Nk5/Hmx). Of these genes, only NKX2.6NKX3.1, LBX1TLX1 and LBX2TLX2 remain tightly linked in humans. However, it is currently unclear whether this is unique to the human genome as we do not know which of these Nk genes are clustered in other vertebrates. This makes it difficult to assess whether the remaining linkages are due to selective pressures or because chance rearrangements have “missed” certain genes. In this paper, we identify all of the paralogs of these ancestrally clustered NK genes in several distinct vertebrates. We demonstrate that tight linkages of Lbx1Tlx1, Lbx2Tlx2 and Nkx3.1Nkx2.6 have been widely maintained in both the ray-finned and lobe-finned fish lineages. Moreover, the recently duplicated Hmx2Hmx3 genes are also tightly linked. Finally, we show that Lbx1Tlx1 and Hmx2Hmx3 are flanked by highly conserved noncoding elements, suggesting that shared regulatory regions may have resulted in evolutionary pressure to maintain these linkages. Consistent with this, these pairs of genes have overlapping expression domains. In contrast, Lbx2Tlx2 and Nkx3.1Nkx2.6, which do not seem to be coexpressed, are also not associated with conserved noncoding sequences, suggesting that an alternative mechanism may be responsible for the continued clustering of these genes.


Nkx Msx Lbx Tlx Hmx CNE 



This work was supported in part by a Royal Society University Research Fellowship to KEL and by a EU grant # LSH-CT-2004-511978 Myores to SD.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Karl R. Wotton
    • 1
    • 3
  • Frida K. Weierud
    • 2
  • José L. Juárez-Morales
    • 2
  • Lúcia E. Alvares
    • 1
    • 4
  • Susanne Dietrich
    • 1
    • 5
  • Katharine E. Lewis
    • 2
  1. 1.Department of Craniofacial DevelopmentKing’s College LondonLondonUK
  2. 2.Department of Physiology, Development and NeuroscienceCambridge UniversityCambridgeUK
  3. 3.EMBL/CRG Systems Biology Research UnitCentre for Genomic Regulation (CRG)BarcelonaSpain
  4. 4.Department of Histology and Embryology, Institute of BiologyState University of Campinas (UNICAMP)São PauloBrazil
  5. 5.School of Biomedical and Health SciencesKing’s College LondonLondonUK

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