A Mouse Cerberus/Dan-Related Gene Family

Abstract

TheXenopus cerberusgene is able to induce ectopic heads inXenopusembryos. At the time of its identification, cerberus shared significant homology with only one other protein, the putative rat tumor suppressor protein Dan. Sequence analysis has revealed that cerberus and Dan are members of a family of predicted secreted proteins, here called the can family. The identification of a can-family member in the nematodeCaenorhabditis elegans, CeCan1,suggests that this family is of ancient origin. In the mouse, there are at least five family members:Cer1, Drm, PRDC, Dan,andDte.These genes are expressed in patterns that suggest that they may play important roles in patterning the developing embryo.Cer1marks the anterior visceral endoderm at E6.5.Dteis expressed asymmetrically in the developing node.Danis first seen in the head mesoderm of early head fold stage embryos andDrmis expressed in the lateral paraxial mesoderm at E8.5. The region of homology shared by these genes, here called the can domain, closely resembles the cysteine knot motif found in a number of signaling molecules, such as members of the TGFβ superfamily. Epitope-tagged versions of Cer1 show that, unlike in TGFβ superfamily members, the cysteine knot motif is not processed away from a proprotein. Recent experiments inXenopushave suggested that cerberus may act as an inhibitor of BMP signaling. To examine this further, the ability of Dan, Cer1, and human DRM to attenuate Bmp4 signaling has been assessed in P19 cells using pTlx-Lux, a BMP-responsive reporter. All three genes are able to inhibit Bmp4 signaling. These data suggest that the different family members may act to modulate the action of TGFβ family members during development.