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  - 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  - 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  - Rödel, Claudia Jasmin
A1  - Otten, Cecile
A1  - Donat, Stefan
A1  - Lourenço, Marta Sofia Rocha
A1  - Fischer, Dorothea
A1  - Kuropka, Benno
A1  - Paolini, Alessio
A1  - Freund, Christian
A1  - Abdelilah-Seyfried, Salim
T1  - Blood Flow Suppresses Vascular Anomalies in a Zebrafish Model of Cerebral Cavernous Malformations
JF  - Circulation Research
N2  - RATIONALE: Pathological biomechanical signaling induces vascular anomalies including cerebral cavernous malformations (CCM), which are caused by a clonal loss of CCM1/KRIT1 (Krev interaction trapped protein 1), CCM2/MGC4607, or CCM3/PDCD10. Why patients typically experience lesions only in lowly perfused venous capillaries of the cerebrovasculature is completely unknown. OBJECTIVE: In contrast, animal models with a complete loss of CCM proteins lack a functional heart and blood flow and exhibit vascular anomalies within major blood vessels as well. This finding raises the possibility that hemodynamics may play a role in the context of this vascular pathology. METHODS AND RESULTS: Here, we used a genetic approach to restore cardiac function and blood flow in a zebrafish model of CCM1. We find that blood flow prevents cardiovascular anomalies including a hyperplastic expansion within a large Ccm1-deficient vascular bed, the lateral dorsal aorta. CONCLUSIONS: This study identifies blood flow as an important physiological factor that is protective in the cause of this devastating vascular pathology.
KW  - animal models
KW  - cerebral cavernous malformations
KW  - endothelial cell
KW  - hemodynamics
KW  - zebrafish
Y1  - 2019
U6  - https://doi.org/10.1161/CIRCRESAHA.119.315076
SN  - 0009-7330
SN  - 1524-4571
VL  - 125
IS  - 10
SP  - E43
EP  - E54
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Tang, Alan T.
A1  - Sullivan, Katie Rose
A1  - Hong, Courtney C.
A1  - Goddard, Lauren M.
A1  - Mahadevan, Aparna
A1  - Ren, Aileen
A1  - Pardo, Heidy
A1  - Peiper, Amy
A1  - Griffin, Erin
A1  - Tanes, Ceylan
A1  - Mattei, Lisa M.
A1  - Yang, Jisheng
A1  - Li, Li
A1  - Mericko-Ishizuka, Patricia
A1  - Shen, Le
A1  - Hobson, Nicholas
A1  - Girard, Romuald
A1  - Lightle, Rhonda
A1  - Moore, Thomas
A1  - Shenkar, Robert
A1  - Polster, Sean P.
A1  - Roedel, Claudia Jasmin
A1  - Li, Ning
A1  - Zhu, Qin
A1  - Whitehead, Kevin J.
A1  - Zheng, Xiangjian
A1  - Akers, Amy
A1  - Morrison, Leslie
A1  - Kim, Helen
A1  - Bittinger, Kyle
A1  - Lengner, Christopher J.
A1  - Schwaninger, Markus
A1  - Velcich, Anna
A1  - Augenlicht, Leonard
A1  - Abdelilah-Seyfried, Salim
A1  - Min, Wang
A1  - Marchuk, Douglas A.
A1  - Awad, Issam A.
A1  - Kahn, Mark L.
T1  - Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation
JF  - Science Translational Medicine
N2  - Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10. Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with PDCD10 mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of Pdcd10 in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.
Y1  - 2019
U6  - https://doi.org/10.1126/scitranslmed.aaw3521
SN  - 1946-6234
SN  - 1946-6242
VL  - 11
IS  - 520
PB  - American Assoc. for the Advancement of Science
CY  - Washington
ER  - 
TY  - JOUR
A1  - Lombardo, Verónica A.
A1  - Heise, Melina
A1  - Moghtadaei, Motahareh
A1  - Bornhorst, Dorothee
A1  - Männer, Jörg
A1  - Abdelilah-Seyfried, Salim
T1  - Morphogenetic control of zebrafish cardiac looping by Bmp signaling
JF  - Development : Company of Biologists
N2  - Cardiac looping is an essential and highly conserved morphogenetic process that places the different regions of the developing vertebrate heart tube into proximity of their final topographical positions. High-resolution 4D live imaging of mosaically labelled cardiomyocytes reveals distinct cardiomyocyte behaviors that contribute to the deformation of the entire heart tube. Cardiomyocytes acquire a conical cell shape, which is most pronounced at the superior wall of the atrioventricular canal and contributes to S-shaped bending. Torsional deformation close to the outflow tract contributes to a torque-like winding of the entire heart tube between its two poles. Anisotropic growth of cardiomyocytes based on their positions reinforces S-shaping of the heart. During cardiac looping, bone morphogenetic protein pathway signaling is strongest at the future superior wall of the atrioventricular canal. Upon pharmacological or genetic inhibition of bone morphogenetic protein signaling, myocardial cells at the superior wall of the atrioventricular canal maintain cuboidal cell shapes and S-shaped bending is impaired. This description of cellular rearrangements and cardiac looping regulation may also be relevant for understanding the etiology of human congenital heart defects.
KW  - BMP
KW  - Wnt
KW  - Cardiac looping
KW  - Hemodynamics
KW  - Zebrafish
Y1  - 2019
U6  - https://doi.org/10.1242/dev.180091
SN  - 0950-1991
SN  - 1477-9129
VL  - 146
IS  - 22
PB  - The Company of Biologists Ltd
CY  - Cambridge
ER  -