title: Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish.
abstract: The vertebrate heart is one of the first organs to form, and its early function and morphogenesis are crucial for continued embryonic development. Here we analyze the effects of loss of Heart adaptor protein 1 (Hadp1), which we show is required for normal function and morphogenesis of the embryonic zebrafish heart. Hadp1 is a pleckstrin homology (PH)-domain-containing protein whose expression is enriched in embryonic cardiomyocytes. Knockdown of hadp1 in zebrafish embryos reduced cardiac contractility and altered late myocyte differentiation. By using optical mapping and submaximal levels of hadp1 knockdown, we observed profound effects on Ca(2+) handling and on action potential duration in the absence of morphological defects, suggesting that Hadp1 plays a major role in the regulation of intracellular Ca(2+) handling in the heart. Hadp1 interacts with phosphatidylinositol 4-phosphate [PI4P; also known as PtdIns(4)P] derivatives via its PH domain, and its subcellular localization is dependent upon this motif. Pharmacological blockade of the synthesis of PI4P derivatives in vivo phenocopied the loss of hadp1 in zebrafish. Collectively, these results demonstrate that hadp1 is required for normal cardiac function and morphogenesis during embryogenesis, and suggest that hadp1 modulates Ca(2+) handling in the heart through its interaction with phosphatidylinositols.
authors.affiliation: Department of Oncological Sciences and Medicine, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Wythe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurynec
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Urness
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Jones
authors.forename: M Khaled
authors.initials: MK
authors.lastname: Sabeh
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Werdich
authors.forename: Mariko
authors.initials: M
authors.lastname: Sato
authors.forename: H Joseph
authors.initials: HJ
authors.lastname: Yost
authors.forename: David J
authors.initials: DJ
authors.lastname: Grunwald
authors.forename: Calum A
authors.initials: CA
authors.lastname: Macrae
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000818:Animals; D019521:Body Patterning; D001919:Bradycardia / Q000196:embryology / Q000503:physiopathology; D020013:Calcium Signaling; D002302:Cardiac Output; D002452:Cell Count; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006321:Heart / Q000196:embryology / Q000502:physiology; D006801:Humans; D009124:Muscle Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D038081:Organogenesis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013347:Subcellular Fractions / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D029961:Zebrafish Proteins; C568917:plekha7a protein, zebrafish; D019870:1-Phosphatidylinositol 4-Kinase