Expression pattern of Dkk-1 during mouse limb development.

dkk-1 has recently been identified as a secreted protein in Xenopus laevis which is sufficient and necessary to cause head induction by antagonizing Wnt signalling (Glinka et al., 1998, Nature 391, 357-362). Consistent with such a role dkk-1 is expressed in the Spemann organizer of the early frog gastrula. Later, expression can be observed in an endomesodermal domain corresponding to the prospective prechordal plate, in two longitudinal stripes flanking the anterior chordamesoderm and in the precursors of the liver. At late neurula stage expression occurs in the prechordal plate adjacent to the prospective forebrain and eyes and in a stripe corresponding to the forming somites. dkk-1 is part of a gene family with at least three family members which is conserved between species. Its mouse homologue, Dkk-1, is first expressed at embryonic day (E) 6.5 in mesodermal cells adjacent to the embryonic/extraembryonic junction. Starting at E7.5 transcripts can be detected in the head mesoderm and at E8.5 additionally in developing somites (Glinka et al., 1998, Nature 391, 357-362). In this study we focus on the highly dynamic pattern of Dkk-1 mRNA distribution during mouse limb development from E9.0-E14.5. The other currently known family members, Dkk-2 and -3, are not expressed in the limb bud before E11.5 (C. Niehrs, pers. commun.) while the limb pattern is established. We show that Dkk-1 expression starts with the first sign of forelimb budding, whereas in the presumptive hindlimb region transcription becomes already apparent before the limb starts to bud out. Expression then becomes confined to two mesenchymal domains at E10.5 and E11.5. Using double-whole mount in situ hybridization we show that the posterior Dkk-1 expression domain initially overlaps with that of Shh, one of the key signalling molecules in limb development. Later, the two expression domains become separated. At E12.5-E14.5 Dkk-1 transcripts are restricted to the interdigital mesenchyme.