TY  - JOUR
A1  - Uribe, Veronica
A1  - Ramadass, Radhan
A1  - Dogra, Deepika
A1  - Rasouli, S. Javad
A1  - Gunawan, Felix
A1  - Nakajima, Hiroyuki
A1  - Chiba, Ayano
A1  - Reischauer, Sven
A1  - Mochizuki, Naoki
A1  - Stainier, Didier Y. R.
T1  - In vivo analysis of cardiomyocyte proliferation during trabeculation
JF  - Development : Company of Biologists
N2  - Cardiomyocyte proliferation is crucial for cardiac growth, patterning and regeneration; however, few studies have investigated the behavior of dividing cardiomyocytes in vivo. Here, we use time-lapse imaging of beating hearts in combination with the FUCCI system to monitor the behavior of proliferating cardiomyocytes in developing zebrafish. Confirming in vitro observations, sarcomere disassembly, as well as changes in cell shape and volume, precede cardiomyocyte cytokinesis. Notably, cardiomyocytes in zebrafish embryos and young larvae mostly divide parallel to the myocardial wall in both the compact and trabecular layers, and cardiomyocyte proliferation is more frequent in the trabecular layer. While analyzing known regulators of cardiomyocyte proliferation, we observed that the Nrg/ErbB2 and TGF beta signaling pathways differentially affect compact and trabecular layer cardiomyocytes, indicating that distinct mechanisms drive proliferation in these two layers. In summary, our data indicate that, in zebrafish, cardiomyocyte proliferation is essential for trabecular growth, but not initiation, and set the stage to further investigate the cellular and molecular mechanisms driving cardiomyocyte proliferation in vivo.
KW  - Heart development
KW  - Cardiomyocyte proliferation
KW  - Trabeculation
KW  - Sarcomere
Y1  - 2018
U6  - https://doi.org/10.1242/dev.164194
SN  - 0950-1991
SN  - 1477-9129
VL  - 145
IS  - 14
PB  - Company biologists LTD
CY  - Cambridge
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  - 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  - Grdseloff, Nastasja
A1  - Boulday, Gwenola
A1  - Roedel, Claudia J.
A1  - Otten, Cecile
A1  - Vannier, Daphne Raphaelle
A1  - Cardoso, Cecile
A1  - Faurobert, Eva
A1  - Dogra, Deepika
A1  - Tournier-Lasserve, Elisabeth
A1  - Abdelilah-Seyfried, Salim
T1  - Impaired retinoic acid signaling in cerebral cavernous malformations
JF  - Scientific reports
N2  - The capillary-venous pathology cerebral cavernous malformation (CCM) is caused by loss of CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations of CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and in-operable regions of the central nervous system. Previous pharmacological suppression screens in disease models of CCM led to the discovery that treatment with retinoic acid improved CCM phenotypes. This finding raised a need to investigate the involvement of retinoic acid in CCM and test whether it has a curative effect in preclinical mouse models. Here, we show that components of the retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models of CCM. We complemented this analysis by pharmacologically modifying retinoic acid levels in zebrafish and human endothelial cell models of CCM, and in acute and chronic mouse models of CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrafish showed positive effects when retinoic acid levels were increased. However, therapeutic approaches to prevent the development of vascular lesions in adult chronic murine models of CCM were drug regiment-sensitive, possibly due to adverse developmental effects of this hormone. A treatment with high doses of retinoic acid even worsened CCM lesions in an adult chronic murine model of CCM. This study provides evidence that retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modification of retinoic acid levels can alleviate CCM phenotypes.
KW  - Developmental biology
KW  - Molecular medicine
Y1  - 2023
U6  - https://doi.org/10.1038/s41598-023-31905-0
SN  - 2045-2322
VL  - 13
IS  - 1
PB  - Nature Portfolio
CY  - Berlin
ER  -