Joint Research Division Vascular Biology of the Medical Faculty Mannheim (CBTM), University of Heidelberg,
and the German Cancer Research Center (DKFZ-ZMBH Alliance)
Developmental Vascular Biology
Research InterestWe are studying how endothelial cells form a mature vascular network. We focus on the roles of Delta-Notch signaling during vascular development and differentiation. This cascade promotes arterial cell fate and restrains vascular sprouting and branching. However, the detailed mechanisms, how these functions are fulfilled, are still not resolved. Our lab aims to clarify the functional roles of Notch receptors and ligands during the process of arterial vs. venous differentiation, sprouting angiogenesis, vascular maturation and maintenance. These studies are performed in primary human endothelial cells, pericytes and vascular smooth muscle cells as well as in transgenic mouse models. This should lead to a better understanding of vascular physiology and pathophysiology. Our long-term goal is the transfer of such basic research results into clinical applications for a better treatment of devastating diseases like solid tumors.
Delta-Notch signaling: Interaction of Notch receptors with ligands induces cleavage of the receptor leading to liberation of the intracellular domain followed by induction of target genes like Hes and Hey.
Current Projects:¨ Functional analyses of Notch ligands in the cardiovascular system ¨ Identification and functional characterization of novel Notch interacting proteins ¨ Identification and functional characterization of novel Notch target genes ¨ Deciphering the biology of vascular malformations with an emphasis on cerebral cavernous malformations
Please contact Dr. Andreas Fischer for further information: fischer(at)angiogenese.de
The Dll4-Notch-Hey1/2 signaling cascade promotes arterial cell fate (see Diez et al., Exp Cell Res, 2007).
Loss of the Notch target genes Hey1 and HeyL impairs endothelial to mesenchymal transformation leading to severe congenital heart defects (see Fischer at al., Circ Res, 2007).
Loss of the Notch target gene Hey2 causes an enlarged atrio-ventricular canal (see Ruthenberg et al., Development, 2006), ectopic expression of atrial genes in the ventricular myocardium (see Fischer et al., Mol Cell Biol, 2005) and congenital heart defects (see Gessler et al., Curr Biol, 2002).
The Notch target genes Hey1 and Hey2 are essential regulators of angiogenesis and arterial differentiation (see Fischer et al., Genes Dev, 2004).
Publications
- Research papers -Thoma E, Wagner T, Fischer A, Weber I, Schartl M. Ectopic expression of single transcription factors directs differentiation of a Medaka spermatogonial cell line. Stem Cells and Development 2010 in press.
Schleider E, Stahl S, Wüstehube J, Walter U, Fischer A, Felbor U. Evidence for anti-angiogenic and pro-survival functions of the cerebral cavernous malformation protein 3. Neurogenetics 2010; Sep 23. [Epub ahead of print].
Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A. Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling.Proc Natl Acad Sci U S A. 2010;107(28):12640-5.
Brütsch R, Liebler SS, Wüstehube J, Bartol A, Herberich SE, Adam MG, Telzerow A, Augustin HG, Fischer A. The integrin cytoplasmic domain-associated protein-1 (ICAP1) attenuates sprouting angiogenesis. Circ Res. 2010; 107(5):592-601.
Coulpier F, Le Crom S, Maro GS, Manent J, Giovannini M, Maciorowski Z, Fischer A, Gessler M, Charnay P, Topilko P.Novel features of boundary cap cells revealed by the analysis of newly identified molecular markers. Glia 2009; 57(13):1450-7.
Fischer A, Steidl C, Wagner TU, Lang E, Jakob PM, Friedl P, Knobeloch KP, Gessler M. Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res 2007;100 (6):856-63.
Diez H, Fischer A, Winkler A, Hu CJ, Hatzopoulos AK, Breier G, Gessler M. Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp Cell Res 2007;313 (1):1-9.
Rutenberg JB, Fischer A, Jia H, Gessler M, Zhong TP, Mercola M. Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development 2006;133 (21):4381-90.
Fischer A, Klattig J, Kneitz B, Diez H, Maier M, Holtmann B, Englert C, Gessler M. Hey basic helix-loop-helix transcription factors are repressors of GATA4 and GATA6 and restrict expression of the GATA target gene ANF in fetal hearts. Mol Cell Biol 2005;25 (20):8960-70.
Schlaeger TM, Schuh A, Flitter S, Fisher A, Mikkola H, Orkin SH, Vyas P, Porcher C. Decoding hematopoietic specificity in the helix-loop-helix domain of the transcription factor SCL/Tal-1. Mol Cell Biol 2004;24 (17):7491-502.
Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 2004;18 (8):901-11.
Fischer A, Klamt B, Schumacher N, Glaeser C, Hansmann I, Fenge H, Gessler M. Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome. Mamm Genome 2004;15 (9):711-6.
Van Wayenbergh R, Taelman V, Pichon B, Fischer A, Kricha S, Gessler M, Christophe D, Bellefroid EJ. Identification of BOIP, a novel cDNA highly expressed during spermatogenesis that encodes a protein interacting with the orange domain of the hairy-related transcription factor HRT1/Hey1 in Xenopus and mouse. Dev Dyn 2003;228 (4):716-25.
Popp H, Kalb R, Fischer A, Lobitz S, Kokemohr I, Hanenberg H, Schindler D. Screening Fanconi anemia lymphoid cell lines of non-A, C, D2, E, F, G subtypes for defects in BRCA2/FANCD1. Cytogenet Genome Res 2003;103 (1-2):54-7.
Gessler M, Knobeloch KP, Helisch A, Amann K, Schumacher N, Rohde E, Fischer A, Leimeister C. Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 -/- mice. Curr Biol 2002;12 (18):1601-4.
Fischer A, Leimeister C, Winkler C, Schumacher N, Klamt B, Elmasri H, Steidl C, Maier M, Knobeloch KP, Amann K, Helisch A, Sendtner M, Gessler M. Hey bHLH factors in cardiovascular development. Cold Spring Harb Symp Quant Biol 2002;67:63-70.
Leimeister C, Dale K, Fischer A, Klamt B, Hrabe de Angelis M, Radtke F, McGrew MJ, Pourquie O, Gessler M. Oscillating expression of c-Hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors. Dev Biol 2000;227 (1):91-103.
- Reviews –
Fischer A,
Gessler M. Delta - Notch - and then? Protein interactions and proposed
modes of repression by Hey and Hes bHLH factors.
Fischer A, Gessler M. Notch-Regulation der Herzentwicklung. BIOspektrum 2007; in press.
Fischer A. CADASIL: eine Angiopathie verursacht durch NOTCH3 Mutationen. Med. Genetik 2006;18 (4):14-8.
Fischer A, Gessler M. Hey genes in cardiovascular development. Trends Cardiovasc Med 2003;13 (6):221-6.
- Books –
Schremmer C, Fischer A (2009) Physiologie Band 6, Herz und Kreislauf, 3. Auflage, MEDI-LEARN Verlag,
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