@misc{BornhorstAbdelilahSeyfried2021, author = {Bornhorst, Dorothee and Abdelilah-Seyfried, Salim}, title = {Strong as a Hippo's Heart: Biomechanical Hippo Signaling During Zebrafish Cardiac Development}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, publisher = {Universit{\"a}tsverlag Potsdam}, address = {Potsdam}, issn = {1866-8372}, doi = {10.25932/publishup-54873}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-548731}, pages = {1 -- 10}, year = {2021}, abstract = {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.}, language = {en} } @article{BornhorstAbdelilahSeyfried2021, author = {Bornhorst, Dorothee and Abdelilah-Seyfried, Salim}, title = {Strong as a Hippo's Heart: Biomechanical Hippo Signaling During Zebrafish Cardiac Development}, series = {Frontiers in Cell and Developmental Biology}, volume = {9}, journal = {Frontiers in Cell and Developmental Biology}, publisher = {Frontiers Media}, address = {Lausanne, Schweiz}, issn = {2296-634X}, doi = {10.3389/fcell.2021.731101}, pages = {1 -- 10}, year = {2021}, abstract = {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.}, language = {en} } @article{BornhorstXiaNakajimaetal.2019, author = {Bornhorst, Dorothee and Xia, Peng and Nakajima, Hiroyuki and Dingare, Chaitanya and Herzog, Wiebke and Lecaudey, Virginie and Mochizuki, Naoki and Heisenberg, Carl-Philipp and Yelon, Deborah and Abdelilah-Seyfried, Salim}, title = {Biomechanical signaling within the developing zebrafish heart attunes endocardial growth to myocardial chamber dimensions}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, publisher = {Nature Publ. Group}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-019-12068-x}, pages = {10}, year = {2019}, abstract = {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.}, language = {en} } @article{ChapmanLantOhashietal.2019, author = {Chapman, Eric M. and Lant, Benjamin and Ohashi, Yota and Yu, Bin and Schertzberg, Michael and Go, Christopher and Dogra, Deepika and Koskimaki, Janne and Girard, Romuald and Li, Yan and Fraser, Andrew G. and Awad, Issam A. and Abdelilah-Seyfried, Salim and Gingras, Anne-Claude and Derry, William Brent}, title = {A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, publisher = {Nature Publ. Group}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-019-09829-z}, pages = {15}, year = {2019}, abstract = {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.}, language = {en} } @article{CuiSchlesingerSchoenhalsetal.2016, author = {Cui, Huanhuan and Schlesinger, Jenny and Schoenhals, Sophia and Toenjes, Martje and Dunkel, Ilona and Meierhofer, David and Cano, Elena and Schulz, Kerstin and Berger, Michael F. and Haack, Timm and Abdelilah-Seyfried, Salim and Bulyk, Martha L. and Sauer, Sascha and Sperling, Silke R.}, title = {Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA}, series = {Nucleic acids research}, volume = {44}, journal = {Nucleic acids research}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0305-1048}, doi = {10.1093/nar/gkv1244}, pages = {2538 -- 2553}, year = {2016}, abstract = {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.}, language = {en} } @misc{deVinuesaAbdelilahSeyfriedKnausetal.2016, author = {de Vinuesa, Amaya Garcia and Abdelilah-Seyfried, Salim and Knaus, Petra and Zwijsen, An and Bailly, Sabine}, title = {BMP signaling in vascular biology and dysfunction}, series = {New journal of physics : the open-access journal for physics}, volume = {27}, journal = {New journal of physics : the open-access journal for physics}, publisher = {Elsevier}, address = {Oxford}, issn = {1359-6101}, doi = {10.1016/j.cytogfr.2015.12.005}, pages = {65 -- 79}, year = {2016}, abstract = {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.}, language = {en} } @article{DemalHeiseReizetal.2019, author = {Demal, Till Joscha and Heise, Melina and Reiz, Benedikt and Dogra, Deepika and Braenne, Ingrid and Reichenspurner, Hermann and M{\"a}nner, J{\"o}rg and Aherrahrou, Zouhair and Schunkert, Heribert and Erdmann, Jeanette and Abdelilah-Seyfried, Salim}, title = {A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A}, series = {Scientific reports}, volume = {9}, journal = {Scientific reports}, publisher = {Nature Publ. Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/s41598-019-39648-7}, pages = {12}, year = {2019}, abstract = {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.}, language = {en} } @article{DietrichLombardoAbdelilahSeyfried2014, author = {Dietrich, Ann-Christin and Lombardo, Veronica A. and Abdelilah-Seyfried, Salim}, title = {Blood flow and Bmp signaling control endocardial chamber morphogenesis}, series = {Developmental cell}, volume = {30}, journal = {Developmental cell}, number = {4}, publisher = {Cell Press}, address = {Cambridge}, issn = {1534-5807}, doi = {10.1016/j.devcel.2014.06.020}, pages = {367 -- 377}, year = {2014}, abstract = {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.}, language = {en} } @article{DonatLourencoPaolinietal.2018, author = {Donat, Stefan and Lourenco, Marta Sofia Rocha and Paolini, Alessio and Otten, Cecile and Renz, Marc and Abdelilah-Seyfried, Salim}, title = {Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis}, series = {eLife}, volume = {7}, journal = {eLife}, publisher = {eLife Sciences Publications}, address = {Cambridge}, issn = {2050-084X}, doi = {10.7554/eLife.28939}, pages = {22}, year = {2018}, abstract = {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.}, language = {en} } @misc{HaackAbdelilahSeyfried2016, author = {Haack, Timm and Abdelilah-Seyfried, Salim}, title = {The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis}, series = {Development : Company of Biologists}, volume = {143}, journal = {Development : Company of Biologists}, publisher = {Company of Biologists Limited}, address = {Cambridge}, issn = {0950-1991}, doi = {10.1242/dev.131425}, pages = {373 -- 386}, year = {2016}, abstract = {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.}, language = {en} }