Abstract
During vertebrate embryogenesis, a left-right axis is established. The heart, associated vessels and inner organs adopt asymmetric spatial arrangements and morphologies. Secreted growth factors of the TGF-beta family, including nodal, lefty-1 and lefty-2, play crucial roles in establishing left-right asymmetries [1] [2] [3]. In zebrafish, nodal signalling requires the presence of one-eyed pinhead (oep), a member of the EGF-CFC family of membrane-associated proteins [4]. We have generated a mutant allele of cryptic, a mouse EGF-CFC gene [5]. Homozygous cryptic mutants developed to birth, but the majority died during the first week of life because of complex cardiac malformations 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 mutant mice, but neither nodal, lefty-2 nor Pitx2 were expressed in the left lateral plate mesoderm. The laterality defects observed in cryptic(-/-) mice resemble those of mice lacking the type IIB activin receptor or the homeobox-containing factor Pitx2 [6] [7] [8] [9], and are reminiscent of the human asplenic syndrome [10]. Our results provide genetic evidence for a role of cryptic in the signalling cascade that determines left-right asymmetry.
MeSH terms
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Alleles
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Animals
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Animals, Newborn
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Dextrocardia / embryology
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Dextrocardia / genetics
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Embryonic and Fetal Development / genetics*
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Fetal Heart / abnormalities
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Gene Expression Regulation, Developmental
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Genotype
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Growth Substances / physiology*
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Heart Defects, Congenital / embryology
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Heart Defects, Congenital / genetics
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Homeobox Protein PITX2
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Homeodomain Proteins / genetics
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Homeodomain Proteins / physiology
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Intercellular Signaling Peptides and Proteins*
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Left-Right Determination Factors
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Mesoderm / metabolism
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Mice
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Mice, Knockout
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Morphogenesis / genetics*
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Nodal Protein
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Nuclear Proteins*
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Paired Box Transcription Factors
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Recombinant Fusion Proteins / physiology
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Signal Transduction / physiology
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Spleen / abnormalities
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Syndrome
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Transcription Factors / genetics
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Transcription Factors / physiology
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Transforming Growth Factor beta / deficiency
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / physiology
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Transposition of Great Vessels / embryology
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Transposition of Great Vessels / genetics
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Viscera / abnormalities
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Zebrafish Proteins*
Substances
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CFC1 protein, human
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Cfc1 protein, mouse
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Growth Substances
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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LEFTY1 protein, human
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Left-Right Determination Factors
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NODAL protein, human
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Nodal Protein
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Nodal protein, mouse
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Nuclear Proteins
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Paired Box Transcription Factors
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Recombinant Fusion Proteins
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Transcription Factors
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Transforming Growth Factor beta
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Zebrafish Proteins
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homeobox protein PITX1
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homeobox protein PITX3
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tdgf1 protein, zebrafish