TY - GEN A1 - Bornhorst, Dorothee A1 - Abdelilah-Seyfried, Salim T1 - Strong as a Hippo’s Heart: Biomechanical Hippo Signaling During Zebrafish Cardiac Development T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - The heart is comprised of multiple tissues that contribute to its physiological functions. During development, the growth of myocardium and endocardium is coupled and morphogenetic processes within these separate tissue layers are integrated. Here, we discuss the roles of mechanosensitive Hippo signaling in growth and morphogenesis of the zebrafish heart. Hippo signaling is involved in defining numbers of cardiac progenitor cells derived from the secondary heart field, in restricting the growth of the epicardium, and in guiding trabeculation and outflow tract formation. Recent work also shows that myocardial chamber dimensions serve as a blueprint for Hippo signaling-dependent growth of the endocardium. Evidently, Hippo pathway components act at the crossroads of various signaling pathways involved in embryonic zebrafish heart development. Elucidating how biomechanical Hippo signaling guides heart morphogenesis has direct implications for our understanding of cardiac physiology and pathophysiology. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1236 KW - Hippo signaling KW - Yap1/Wwtr1 (Taz) KW - cardiac development KW - mechanobiology KW - endocardium KW - myocardium KW - zebrafish KW - intra-organ-communication Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-548731 SN - 1866-8372 SP - 1 EP - 10 PB - Universitätsverlag Potsdam CY - Potsdam ER - TY - JOUR A1 - Bornhorst, Dorothee A1 - Abdelilah-Seyfried, Salim T1 - Strong as a Hippo’s Heart: Biomechanical Hippo Signaling During Zebrafish Cardiac Development JF - Frontiers in Cell and Developmental Biology N2 - The heart is comprised of multiple tissues that contribute to its physiological functions. During development, the growth of myocardium and endocardium is coupled and morphogenetic processes within these separate tissue layers are integrated. Here, we discuss the roles of mechanosensitive Hippo signaling in growth and morphogenesis of the zebrafish heart. Hippo signaling is involved in defining numbers of cardiac progenitor cells derived from the secondary heart field, in restricting the growth of the epicardium, and in guiding trabeculation and outflow tract formation. Recent work also shows that myocardial chamber dimensions serve as a blueprint for Hippo signaling-dependent growth of the endocardium. Evidently, Hippo pathway components act at the crossroads of various signaling pathways involved in embryonic zebrafish heart development. Elucidating how biomechanical Hippo signaling guides heart morphogenesis has direct implications for our understanding of cardiac physiology and pathophysiology. KW - Hippo signaling KW - Yap1/Wwtr1 (Taz) KW - cardiac development KW - mechanobiology KW - endocardium KW - myocardium KW - zebrafish KW - intra-organ-communication Y1 - 2021 U6 - https://doi.org/10.3389/fcell.2021.731101 SN - 2296-634X VL - 9 SP - 1 EP - 10 PB - Frontiers Media CY - Lausanne, Schweiz ER - TY - JOUR A1 - Bornhorst, Dorothee A1 - Xia, Peng A1 - Nakajima, Hiroyuki A1 - Dingare, Chaitanya A1 - Herzog, Wiebke A1 - Lecaudey, Virginie A1 - Mochizuki, Naoki A1 - Heisenberg, Carl-Philipp A1 - Yelon, Deborah A1 - Abdelilah-Seyfried, Salim T1 - Biomechanical signaling within the developing zebrafish heart attunes endocardial growth to myocardial chamber dimensions JF - Nature Communications N2 - Intra-organ communication guides morphogenetic processes that are essential for an organ to carry out complex physiological functions. In the heart, the growth of the myocardium is tightly coupled to that of the endocardium, a specialized endothelial tissue that lines its interior. Several molecular pathways have been implicated in the communication between these tissues including secreted factors, components of the extracellular matrix, or proteins involved in cell-cell communication. Yet, it is unknown how the growth of the endocardium is coordinated with that of the myocardium. Here, we show that an increased expansion of the myocardial atrial chamber volume generates higher junctional forces within endocardial cells. This leads to biomechanical signaling involving VE-cadherin, triggering nuclear localization of the Hippo pathway transcriptional regulator Yap1 and endocardial proliferation. Our work suggests that the growth of the endocardium results from myocardial chamber volume expansion and ends when the tension on the tissue is relaxed. Y1 - 2019 U6 - https://doi.org/10.1038/s41467-019-12068-x SN - 2041-1723 VL - 10 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Chapman, Eric M. A1 - Lant, Benjamin A1 - Ohashi, Yota A1 - Yu, Bin A1 - Schertzberg, Michael A1 - Go, Christopher A1 - Dogra, Deepika A1 - Koskimaki, Janne A1 - Girard, Romuald A1 - Li, Yan A1 - Fraser, Andrew G. A1 - Awad, Issam A. A1 - Abdelilah-Seyfried, Salim A1 - Gingras, Anne-Claude A1 - Derry, William Brent T1 - A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis JF - Nature Communications N2 - Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism. We reveal that KRI-1 exists in a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway. This allows the KLF-3 transcription factor to facilitate expression of the SLC39 zinc transporter gene zipt-2.3, which functions to sequester zinc in the intestine. Ablation of KRI-1 results in reduced zinc sequestration in the intestine, inhibition of IR-induced MPK-1/ERK1 activation, and apoptosis in the germline. Zinc localization is also perturbed in the vasculature of krit1(-/-) zebrafish, and SLC39 zinc transporters are mis-expressed in Cerebral Cavernous Malformations (CCM) patient tissues. This study provides new insights into the regulation of apoptosis by cross-tissue communication, and suggests a link between zinc localization and CCM disease. Y1 - 2019 U6 - https://doi.org/10.1038/s41467-019-09829-z SN - 2041-1723 VL - 10 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Cui, Huanhuan A1 - Schlesinger, Jenny A1 - Schoenhals, Sophia A1 - Toenjes, Martje A1 - Dunkel, Ilona A1 - Meierhofer, David A1 - Cano, Elena A1 - Schulz, Kerstin A1 - Berger, Michael F. A1 - Haack, Timm A1 - Abdelilah-Seyfried, Salim A1 - Bulyk, Martha L. A1 - Sauer, Sascha A1 - Sperling, Silke R. T1 - Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA JF - Nucleic acids research N2 - DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure. Y1 - 2016 U6 - https://doi.org/10.1093/nar/gkv1244 SN - 0305-1048 SN - 1362-4962 VL - 44 SP - 2538 EP - 2553 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - de Vinuesa, Amaya Garcia A1 - Abdelilah-Seyfried, Salim A1 - Knaus, Petra A1 - Zwijsen, An A1 - Bailly, Sabine T1 - BMP signaling in vascular biology and dysfunction JF - New journal of physics : the open-access journal for physics N2 - The vascular system is critical for developmental growth, tissue homeostasis and repair but also for tumor development. Bone morphogenetic protein (BMP) signaling has recently emerged as a fundamental pathway of the endothelium by regulating cardiovascular and lymphatic development and by being causative for several vascular dysfunctions. Two vascular disorders have been directly linked to impaired BMP signaling: pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia. Endothelial BMP signaling critically depends on the cellular context, which includes among others vascular heterogeneity, exposure to flow, and the intertwining with other signaling cascades (Notch, WNT, Hippo and hypoxia). The purpose of this review is to highlight the most recent findings illustrating the clear need for reconsidering the role of BMPs in vascular biology. (C) 2015 Elsevier Ltd. All rights reserved. KW - Bone morphogenetic proteins (BMP) KW - Signaling KW - Vasculature KW - Development KW - Disease Y1 - 2016 U6 - https://doi.org/10.1016/j.cytogfr.2015.12.005 SN - 1359-6101 SN - 1879-0305 VL - 27 SP - 65 EP - 79 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Demal, Till Joscha A1 - Heise, Melina A1 - Reiz, Benedikt A1 - Dogra, Deepika A1 - Braenne, Ingrid A1 - Reichenspurner, Hermann A1 - Männer, Jörg A1 - Aherrahrou, Zouhair A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Abdelilah-Seyfried, Salim T1 - A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A JF - Scientific reports N2 - The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein’s anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aap.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology. Y1 - 2019 U6 - https://doi.org/10.1038/s41598-019-39648-7 SN - 2045-2322 VL - 9 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Dietrich, Ann-Christin A1 - Lombardo, Veronica A. A1 - Abdelilah-Seyfried, Salim T1 - Blood flow and Bmp signaling control endocardial chamber morphogenesis JF - Developmental cell N2 - During heart development, the onset of heartbeat and blood flow coincides with a ballooning of the cardiac chambers. Here, we have used the zebrafish as a vertebrate model to characterize chamber ballooning morphogenesis of the endocardium, a specialized population of endothelial cells that line the interior of the heart. By combining functional manipulations, fate mapping studies, and high-resolution imaging, we show that endocardial growth occurs without an influx of external cells. Instead, endocardial cell proliferation is regulated, both by blood flow and by Bmp signaling, in a manner independent of vascular endothelial growth factor (VEGF) signaling. Similar to myocardial cells, endocardial cells obtain distinct chamber-specific and inner- versus outer-curvature-specific surface area sizes. We find that the hemodynamic-sensitive transcription factor Klf2a is involved in regulating endocardial cell morphology. These findings establish the endocardium as the flow-sensitive tissue in the heart with a key role in adapting chamber growth in response to the mechanical stimulus of blood flow. Y1 - 2014 U6 - https://doi.org/10.1016/j.devcel.2014.06.020 SN - 1534-5807 SN - 1878-1551 VL - 30 IS - 4 SP - 367 EP - 377 PB - Cell Press CY - Cambridge ER - TY - JOUR A1 - Donat, Stefan A1 - Lourenco, Marta Sofia Rocha A1 - Paolini, Alessio A1 - Otten, Cecile A1 - Renz, Marc A1 - Abdelilah-Seyfried, Salim T1 - Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis JF - eLife N2 - Endothelial cells respond to different levels of fluid shear stress through adaptations of their mechanosensitivity. Currently, we lack a good understanding of how this contributes to sculpting of the cardiovascular system. Cerebral cavernous malformation (CCM) is an inherited vascular disease that occurs when a second somatic mutation causes a loss of CCM1/KRIT1, CCM2, or CCM3 proteins. Here, we demonstrate that zebrafish Krit1 regulates the formation of cardiac valves. Expression of heg1, which encodes a binding partner of Krit1, is positively regulated by blood-flow. In turn, Heg1 stabilizes levels of Krit1 protein, and both Heg1 and Krit1 dampen expression levels of klf2a, a major mechanosensitive gene. Conversely, loss of Krit1 results in increased expression of klf2a and notch1b throughout the endocardium and prevents cardiac valve leaflet formation. Hence, the correct balance of blood-flow-dependent induction and Krit1 protein mediated repression of klf2a and notch1b ultimately shapes cardiac valve leaflet morphology. Y1 - 2018 U6 - https://doi.org/10.7554/eLife.28939 SN - 2050-084X VL - 7 PB - eLife Sciences Publications CY - Cambridge ER - TY - JOUR A1 - Haack, Timm A1 - Abdelilah-Seyfried, Salim T1 - The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis JF - Development : Company of Biologists N2 - Endocardial cells are cardiac endothelial cells that line the interior of the heart tube. Historically, their contribution to cardiac development has mainly been considered from a morphological perspective. However, recent studies have begun to define novel instructive roles of the endocardium, as a sensor and signal transducer of biophysical forces induced by blood flow, and as an angiocrine signalling centre that is involved in myocardial cellular morphogenesis, regeneration and reprogramming. In this Review, we discuss how the endocardium develops, how endocardial-myocardial interactions influence the developing embryonic heart, and how the dysregulation of blood flowresponsive endocardial signalling can result in pathophysiological changes. KW - Endocardium KW - Cardiac development KW - Hemodynamics KW - Bmp KW - Kruppel-like factor 2 KW - Vegf KW - Mechanotransduction KW - Zebrafish KW - Mouse Y1 - 2016 U6 - https://doi.org/10.1242/dev.131425 SN - 0950-1991 SN - 1477-9129 VL - 143 SP - 373 EP - 386 PB - Company of Biologists Limited CY - Cambridge ER -