Interactive Fly, Drosophila

Developmental roles of Cerberus, a divergent member of the TGF-beta family

Xenopus cerberus (Xcer) is a cytokine expressed in anterior mesendoderm overlapping and surrounding Spemann's gastrula organizer. When misexpressed in blastomeres, Xcer can induce ectopic heads with well-defined brain, cement gland, olfactory placodes, cyclopic eye, and occasionally, a liver and heart. The identification of mCer-1, a murine gene related to cerberus, is reported. Both mCer-1 and Xcer appear to belong to the cystine knot superfamily, which includes TGF betas and BMPs. In Xenopus animal cap assays, mCer-1 and Xcer induce cement glands and markers of anterior neural tissue and endoderm, characteristic of BMP inhibition. Furthermore, both antagonize the ventrolateral mesoderm-inducing activity of coexpressed BMP4. In mouse embryos, mCer-1 is expressed at early gastrulation in a stripe of primitive endoderm along the future anterior side of the egg cylinder, a region essential for anterior patterning. A second phase of expression is detected in anterior embryonic mesendoderm; by late-streak stages, most of the anterior half of the embryo is positive, except for the node and cardiac progenitors. Expression is later seen in the cranial portion of the two most-recently formed somites and in two stripes within presomitic mesoderm. In embryos lacking Otx2, a homeogene with a demonstrated role in anterior patterning, mCer-1, is still expressed in an anterior zone, although often abnormally. The data suggest that mCer-1 shares structural, functional, and expression characteristics with Xcer and may participate in patterning the anterior of the embryo and nascent somite region, in part, through a BMP-inhibitory mechanism (Biben, 1998).

Gremlin, a novel antagonist of bone morphogenetic protein (BMP) signaling that is expressed in the neural crest has been isolated using a Xenopus expression-cloning screen. Gremlin belongs to a novel gene family that includes the head-inducing factor Cerberus and the tumor suppressor DAN. All family members are secreted proteins and they act as BMP antagonists in embryonic explants. Support is provided for the model that Gremlin, Cerberus, and DAN block BMP signaling by binding BMPs, preventing them from interacting with their receptors. In addition, Cerberus alone blocks signaling by Activin- and Nodal-like members of the TGF beta superfamily. Therefore, it is proposed that Gremlin, Cerberus, and DAN control diverse processes in growth and development by selectively antagonizing the activities of different subsets of the TGF beta ligands (Hsu, 1998).

Embryological and genetic evidence indicates that the vertebrate head is induced by a different set of signals from those that organize trunk-tail development. The gene cerberus encodes a secreted protein that is expressed in anterior endoderm and has the unique property of inducing ectopic heads in the absence of trunk structures. The cerberus protein functions as a multivalent growth-factor antagonist in the extracellular space: it binds to Nodal, BMP and Wnt proteins via independent sites. The expression of cerberus during gastrulation is activated by earlier nodal-related signals in endoderm and by Spemann-organizer factors that repress signaling by BMP and Wnt. In order for the head territory to form, it is proposed that signals involved in trunk development, such as those involving BMP, Wnt and Nodal proteins, must be inhibited in rostral regions (Piccolo, 1999).

The Xenopus cerberus gene is able to induce ectopic heads in Xenopus embryos. 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 nematode Caenorhabditis elegans, CeCan1, suggests that this family is of ancient origin. In the mouse, there are at least five family members: Cer1, Drm, PRDC, Dan, and Dte. These genes are expressed in patterns that suggest they may play important roles in patterning the developing embryo. Cer1 marks the anterior visceral endoderm at E6.5. Dte is expressed asymmetrically in the developing node. Dan is first seen in the head mesoderm of early head fold stage embryos and Drm is 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 TGFbeta superfamily. Epitope-tagged versions of Cer1 show that the cysteine knot motif is not processed away from a proprotein; this is unlike the case in TGFbeta superfamily members. Recent experiments in Xenopus have 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 TGFbeta family members during development (Pearce, 1999).

DAN, a potential cell cycle regulator and tumor suppressor, is a secreted glycoprotein related to Xenopus cerberus. DAN, cerberus, its mouse relative Cer-1/cer-l/Cerberus-like/Cerr1, and the recently described factor DRM/Gremlin, appear to be members of the cystine knot superfamily, which includes TGFbetas and BMPs. Like cerberus and mCer-1, DAN induces cement glands as well as markers of anterior neural tissue and endoderm in Xenopus animal cap assays, features of BMP signaling blockade. During mouse embryogenesis, Dan is expressed from E8.5 in cranial mesenchyme and somites, then later in limb and facial mesenchyme. The pattern in somites is highly dynamic, with transcripts initially localized to the caudal half of the nascent epithelial somite, then, after maturation, to sclerotomal cells adjacent to the neural tube. Dan is also expressed in the developing myotome. The expression domains include sites in which BMP inhibition is known to be important for development. Thus, DAN appears to be a secreted factor belonging to the cystine knot superfamily, and one of a growing number of antagonists acting to modulate BMP signaling during development (Stanley, 1998).

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