Vascular Developmental Biology

Developmental Vascular Biology

Research Interest

We are studying how endothelial cells differentiate to form a mature vascular network. Recently, it was shown that the Delta-Notch signaling pathway is a major regulator of angiogenesis. 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 and sprouting angiogenesis. We are developing a series of endothelial cell lines which miss express individual components of this pathway to analyze their function in vitro. This is accomplished by in vivo experiments in zebrafish and mice. Furthermore, we intend to identify and characterize novel target genes and interacting proteins of this cascade. This should lead to a better understanding how Notch signaling affects blood vessel growth and path the way for development of new strategies to modulate its function.

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:

¨ Genetic analysis of Notch ligands in mice and zebrafish with an emphasis on the cardiovascular system

¨ Analysis of the functional consequences of Notch forward and reverse signaling in endothelial cells

¨ Analyzing spatiotemporal Notch and Delta activities in mice and zebrafish

¨ Identification and functional characterization of novel Notch target genes in endothelial cells

¨ Identification and functional characterization of novel Notch interacting proteins

¨ Analyzing the role of Hey transcription factors during endothelial to mesenchymal transformation (coll. with Prof. Dr. M. Gessler, Würzburg)

Please contact Dr. Andreas Fischer for further information: fischer(at)angiogenese.de

==> CV of Dr. Andreas Fischer

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 -

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;Epub ahead of print.

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.
Nucleid Acids Res. 2007;35(14):4583-96.

Fischer A, Gessler M. Notch-Regulation der Herzentwicklung. BIOspektrum 2007 (13):352-6.

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.