An ancient Wnt-Dickkopf antagonism inHydra

Abstract

The dickkopf (dkk) gene family encodes secreted antagonists of Wnt signalling proteins, which have important functions in the control of cell fate, proliferation, and cell polarity during development. Here, we report the isolation, from a regeneration-specific signal peptide screen, of a novel dickkopf gene from the fresh water cnidarian Hydra. Comparative sequence analysis demonstrates that the Wnt antagonistic subfamily Dkk1/Dkk2/Dkk4 and the non-modulating subfamily Dkk3 separated prior to the divergence of cnidarians and bilaterians. In steady-state Hydra, hydkk1/2/4-expression is inversely related to that of hywnt3a. hydkk1/2/4 is an early injury and regeneration responsive gene, and hydkk1/2/4-expressing gland cells are essential for head regeneration in Hydra, although once the head has regenerated they are excluded from it. Activation of Wnt/␤-Catenin signalling leads to the complete downregulation of hydkk1/2/4 transcripts. When overexpressed in Xenopus, HyDkk1/2/4 has similar Wnt-antagonizing activity to the Xenopus gene Dkk1. Based on the corresponding expression patterns of hydkk1/2/4 and neuronal genes, we suggest that the body column of Hydra is a neurogenic environment suppressing Wnt signalling and facilitating neurogenesis.

Function and biological roles of the Dickkopf family of Wnt modulators

“…Taken together, these observations suggest a deep split into Dkk3 and Dkk1/2/4 gene families during early metazoan evolution, and more recent gene duplications accompanied by functional divergence of the two Dkk subfamilies (Guder et al, 2006).…”

“…In some invertebrate Dkks such as the Hydra ortholog Hydkk1/2/4, only the colipase fold occurs (Guder et al, 2006) and structurefunction analysis of vertebrate Dkks has shown that this domain alone is sufficient for biological activity, that is, Wnt inhibition (Brott and Sokol, 2002;Li et al, 2002;Mao and Niehrs, 2003). The colipase fold also shows the greatest sequence conservation among the Dkks.…”

“…Since then Dkks were identified in other vertebrates including humans as well as in invertebrates such as Dictyostelium, cnidarians, urochordates and ascidians (Hino et al, 2003;Fedders et al, 2004;Guder et al, 2006), but not in Drosophila and Caenorhabditis elegans. Thus, Dkks are an evolutionarily ancient gene family that was already present in the last common ancestor of cnidarians and bilaterians and which was probably secondarily lost during evolution in protostomes.…”

“…Unlike in vertebrates, in Hydra Hydkk1/2/4 only the colipase domain occurs, and this protein is biologically active in Wnt inhibition (Guder et al, 2006). Hydra Dkk3 harbors both conserved domains (Fedders et al, 2004).…”

“…(3) Dkk1, 2, and -4 all regulate Wnt signaling and bind the same effectors, unlike Dkk3 (see below). (4) Two Cnidaria, Hydra and Nematostella, each have only two Dkk genes, one related to vertebrate Dkk1, 2 and -4 (Guder et al, 2006) and one related to vertebrate Dkk3 (Fedders et al, 2004). (5) Human DKK1, 2 and -4 are located within the well-characterized chromosome 4/5/8/10 paralogy group (DKK1 maps to 10q11, DKK2 to 4q25 and DKK4 to 8p11).…”