Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish

Joshua D Wythe; Michael J Jurynec; Lisa D Urness; Christopher A Jones; M. Khaled Sabeh; Andreas A Werdich; Mariko Sato; H. Joseph Yost; David J Grunwald; Calum A MacRae; Dean Y Li

doi:10.1242/dmm.002204

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Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish

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Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish

Joshua D Wythe, Michael J Jurynec, Lisa D Urness, Christopher A Jones, M. Khaled Sabeh, Andreas A Werdich, Mariko Sato, H. Joseph Yost, David J Grunwald, Calum A MacRae, …

Disease models & mechanisms, Vol.4(5), pp.607-621

09/2011

DOI: 10.1242/dmm.002204

PMCID: PMC3180224

PMID: 21628396

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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.

Details

Title: Subtitle: Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish
Creators: Joshua D Wythe - Department of Oncological Sciences and Medicine
Michael J Jurynec - Department of Human Genetics
Lisa D Urness - Department of Human Genetics
Christopher A Jones - Department of Oncological Sciences and Medicine
M. Khaled Sabeh - Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 021115, USA
Andreas A Werdich - Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 021115, USA
Mariko Sato - Department of Neurobiology and Anatomy, and
H. Joseph Yost - Department of Neurobiology and Anatomy, and
David J Grunwald - Department of Human Genetics
Calum A MacRae - Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 021115, USA
Dean Y Li - Department of Oncological Sciences and Medicine
Resource Type: Journal article
Publication Details: Disease models & mechanisms, Vol.4(5), pp.607-621
DOI: 10.1242/dmm.002204
PMID: 21628396
PMCID: PMC3180224
NLM abbreviation: Dis Model Mech
ISSN: 1754-8403
eISSN: 1754-8411
Publisher: The Company of Biologists Limited
Language: English
Date published: 09/2011
Academic Unit: Stead Family Department of Pediatrics
Record Identifier: 9984093480902771

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