A role of the cryptic gene in the correct establishment of the left-right axis

During vertebrate embryogenesis, a left-right axis is established. The hear t, associated vessels and inner organs adopt asymmetric spatial arrangement s and morphologies. Secreted growth factors of the TGF-beta family, includi ng nodal, lefty-1 and lefty-2, play crucial roles in establishing left-righ t asymmetries [1-3], In zebrafish, nodal signalling requires the presence o f one-eyed pinhead (oep), a member of the EGF-CFC family of membrane-associ ated proteins [4]. We have generated a mutant allele of cryptic, a mouse EG F-CFC gene [5]. Homozygous cryptic mutants developed to birth, but the majo rity died during the first week of life because of complex cardiac malforma tions such as malpositioning of the great arteries, and atrial-ventricular septal defects. Moreover, laterality defects, including right isomerism of the lungs, right or left positioning of the stomach and splenic hypoplasia were observed. Nodal gene expression in the node was initiated in cryptic m utant mice, but neither nodal, lefty-2 nor Pitx2 were expressed in the left lateral plate mesoderm, The laterality defects observed in cryptic(-/-) mi ce resemble those of mice lacking the type IIB activin receptor or the home obox-containing factor Pitx2 [6-9], and are reminiscent of the human asplen ic syndrome [10]. Our results provide genetic evidence for a role of crypti c in the signalling cascade that determines left-right asymmetry.