Cerberus regulates left-right asymmetry of the embryonic head and heart.
BACKGROUND
Most of the molecules known to regulate left-right asymmetry in vertebrate embryos are expressed on the left side of the future trunk region of the embryo. Members of the protein family comprising Cerberus and the putative tumour suppressor Dan have not before been implicated in left-right asymmetry. In Xenopus, these proteins have been shown to antagonise members of the transforming growth factor beta (TGF-beta) and Wnt families of signalling proteins.


RESULTS
Chick Cerberus (cCer) was found to be expressed in the left head mesenchyme and in the left flank of the embryo. Expression on the left side of the head was controlled by Sonic hedgehog (Shh) acting through the TGF-beta family member Nodal; in the flank, cCer was also regulated by Shh, but independently of Nodal. Surprisingly, although no known targets of Cerberus are expressed asymmetrically on the right side of the embryo at these stages, misexpression of cCer on this side of the embryo led to upregulation of the transcription factor Pitx2 and reversal of the direction of heart and head turning, apparently as independent events. Consistent with the possibility that cCer may be acting on bilaterally expressed TGF-beta family members such as the bone morphogenetic proteins (BMPs), this result was mimicked by right-sided misexpression of the BMP antagonist, Noggin.


CONCLUSIONS
Our findings suggest that cCer maintains a delicate balance of different TGF-beta family members involved in laterality decisions, and reveal the existence of partially overlapping molecular pathways regulating left-right asymmetry in the head and trunk of the embryo.
Zhu
L
L
Department of Genetics and Development, Columbia University, 701 West 168th Street #1602, New York, New York 10032, USA.
Marvin
M J
MJ
Gardiner
A
A
Lassar
A B
AB
Mercola
M
M
Stern
C D
CD
Levin
M
M
D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D019556:COS Cells; D002352:Carrier Proteins; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology; D006257:Head / Q000196:embryology*; D006321:Heart / Q000196:embryology*; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D008648:Mesoderm / Q000378:metabolism; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D005810:Multigene Family; D055457:Nodal Protein; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics; D000097577:Homeobox Protein PITX2; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D006023:Glycoproteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055457:Nodal Protein; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D011506:Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D000097577:Homeobox Protein PITX2; D000099176:Noggin Protein; C100866:cer1 protein, Xenopus; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3; C054234:chordin