Conservation of gene linkage in dispersed vertebrate NK homeobox clusters

Abstract

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 NKX2.6-NKX3.1, LBX1-TLX1 and LBX2-TLX2 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 Lbx1-Tlx1, Lbx2-Tlx2 and Nkx3.1-Nkx2.6 have been widely maintained in both the ray-finned and lobe-finned fish lineages. Moreover, the recently duplicated Hmx2-Hmx3 genes are also tightly linked. Finally, we show that Lbx1-Tlx1 and Hmx2-Hmx3 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, Lbx2-Tlx2 and Nkx3.1-Nkx2.6, 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.

NKL homeobox genes in leukemia

“…The NKL genes are not strongly clustered on the chromosomes in contrast to the HOXA-D genes, although some NKL genes cluster in pairs. This linkage is conserved through species especially for LBX1-TLX1, LBX2-TLX2, NKX2-6-NKX3-1 and HMX2-HMX3 13 and to a lesser extend for NKX2-1-NKX2-8 and NKX2-2-NKX2-4.…”

“…13 In humans, several NKL genes are loosely gathered over large areas on chromosome bands 2p13, 4p15 -16, 5q35 and 10q23 -26 (Table 1).…”

Remodelling of a homeobox gene cluster by multiple independent gene reunions in Drosophila

“…Evolutionary stability of the lancelet genome at the structural level compared with other deuterostome 24,25 and some protostome lineages, such as those of Diptera 26,27 , point to Tlx-NK7 as the most likely ancestral contiguity in the Bilaterian common ancestor. Further, and unlike in other reconstructions of the NK gene organization in this ancestor 13,15,23 , NK1 was inferred to be adjacent to Msx because of their proximity (B76 kb and three intervening genes) within the scaffold 186 of the D. pulex assembly (Supplementary Data 1 and 2).…”

“…Together with comparative genome data comprising an additional six Bilateria including D. melanogaster, An. gambiae, the red flour beetle, the ragworm, the lancelet and humans 13,15,18,22,23 , we laid out the organization of NK genes within the ProtoNK cluster (Fig. 1).…”

Study on the Developmental Expression ofLbx1Gene inLongissimus Dorsiof Mashen and Large White Pigs

“…Lbx (ladybird-like), originated from a part of Nk homeobox cluster of metazoan, encodes transcription factors which can regulate lots of tissues development, including skeletal muscle, heart, central nervous system and sensory organs (Wotton et al, 2009). Lbx family contains 4 members, which are divergent in different vertebrates.…”