title: santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish.
abstract: During embryogenesis, the myocardial layer of the primitive heart tube grows outward from the endocardial-lined lumen, with new cells added to generate concentric thickness to the wall. This is a key evolutionary step, demarcating vertebrates from more primitive chordates, and is essential for normal cardiac function. Zebrafish embryos with the recessive lethal mutations santa (san) and valentine (vtn) do not thicken, but do add the proper number of cells to the myocardium. Consequently, the heart chambers are huge, constituted of a monolayered myocardium lined by endocardium. This phenotype is similar to that of the heart of glass (heg) mutation, which we described previously as a novel endocardial expressed gene. By positional cloning, we here identify san as the zebrafish homolog of human CCM1, and vtn as the homolog of human CCM2. Dominant mutations of either in humans cause vascular anomalies in the brain, known as cerebral cavernous malformations. The synergistic effects of morpholino pairs indicate that san, vtn and heg are in a genetic pathway, and san and vtn contain protein motifs, NPxY and PTB domain, respectively, known to interact. This suggests that concentric growth of the myocardium, crucial for blood pressure generation, is dictated by a heg-san-vtn signaling pathway.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Mably
authors.forename: Lesley P
authors.initials: LP
authors.lastname: Chuang
authors.forename: Fabrizio C
authors.initials: FC
authors.lastname: Serluca
authors.forename: Manzoor-Ali P K
authors.initials: MA
authors.lastname: Mohideen
authors.forename: Jau-Nian
authors.initials: JN
authors.lastname: Chen
authors.forename: Mark C
authors.initials: MC
authors.lastname: Fishman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D002452:Cell Count; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D004699:Endocardium / Q000166:cytology / Q000196:embryology; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D029961:Zebrafish Proteins; C514536:ccm2 protein, zebrafish; C482644:heg1 protein, zebrafish; C514537:krit1 protein, zebrafish