My main research focus is to understand the mechanisms and molecules involved in axon guidance and the formation of topographic maps in the nervous system, in particular the visual system of chick and mouse.

As a group leader at the Max-Planck-Institute for Developmental Biology, Tübingen, I demonstrated a fundamental role for the EphA/ephrin-A family of receptor tyrosine kinases in topographic mapping of the retinotectal projection. I purified and cloned the ephrinA5 molecule (then termed RAGS), and characterised its role in the topographic targeting of retinal ganglion cell (RGC) axons (Cell 82, 359-370 (1995)). This study essentially founded a field, since it assigned for this first time a function to the large EphA/ephrin-A family as axon guidance molecules. Moreover, it allowed now to challenge on a molecular level the chemoaffinity hypothesis proposed by Roger Sperry.

In the next step, I dissected in vitro the shared and distinct roles of ephrinA5 and the related family member ephrinA2 in organising the pattern of retinal axon projections (EMBO J. 16, 1258-1267 (1997)), and showed that the EphA family is the predominant axon guidance family controlling the retinotectal projection (Eur. J. Neurosci. 10, 1574-1588 (1998)). 

Since multiple Ephs and ephrins are expressed by both RGC axons and in the target, it turned out to be challenging to unravel the mechanisms how ephrinAs control neural connectivity. We discovered an unexpected function of ephrinA molecules co-expressed with EphA receptors on RGC axons in desensitising nasal retinal axons to exogenous ephrinAs in vivo and in vitro (Neuron 22,731-742 (1999); Dev. Biol. 216, 297-311(1999)). It turned out subsequently that this kind of receptor/ligand co-expression is a widespread mechanism controlling axon guidance processes.

We were able to show that ephrinA5 induces the turning of retinal axons in vitro (Development 130, 1635-1643 (2003)), which uncovered the mechanism by which ephrinA5 guides RGC axons.   

During this time I also contributed to the finding that the transcription factor Engrailed is involved in controlling expression of ephrinA genes via its patterning effects on the optic tectum (Curr. Biology 6, 1006 – 1014 (1996)), and that the EphA family plays also in zebrafish an important role in retinotectal map development (Development 124,655-664 (1997)). We have furthermore shown the expression of ephrin-A/EphA molecules after optic nerve lesion in adult mice, which is of potential relevance for regeneration-associated processes (Mech. Dev. 106,119-127 (2001)).

Since becoming a group leader at the MRC Centre for Developmental Neurobiology of King’s College London in 2000, I have started to elucidate signalling pathways of Ephs/ephrins, showing their localisation to lipid rafts (J. Biol. Chem. 276, p6689 (2001)) and demonstrated an important role of Src family kinases as downstream signalling molecules in EphA-mediated repulsion (J. Neurosci. 24, p6248 (2004)).

We demonstrated that a second countergradient system is important for map formation in the visual system, as predicted by modelling approaches of A. Gierer in the 1980s. This activity is established by 'reverse signalling' of ephrinAs expressed on RGC axons and EphAs in the target area (Neuron 47, p57 (2005)). We then clarified in further detail the role of Eph/ephrinA cis interactions on RGC axons (Nature Neuroscience 9, p322 (2006)).

We have shown for the first time a function of the EphA family in axon guidance in the development of the vomeronasal projection, here with ephrinAs as attractant axon guidance receptors (Development 128, 895 (2001) in contrast to the visual system where ephrinAs function as repellent receptors (Neuron 47, p57 (2005), see above).

Towards an understanding of the integration of multiple axon guidance systems, our group has recently identified the TrkB receptor as a candidate ephrinA5 co-receptor (J. Neuroscience 28,12700 (2008)). Further work included the characterisation of the antagonistic functions of proBDNF vs. BDNF on axon branching (Neural Development 2010, Nov 2, 30 (2010)) and the demonstration that the TrkB-mediated induction of RGC axon branching is ephrinA-dependent (Mol. Cell Neurobiol. 47, p131 (2011)). Recently, we have shown that TrkB/BDNF controls axon branching (in part) via up-regulation of miR132  which in turn represses p250GAP (J. Neurosci. 34, p969 (2014)).  

Present work includes the characterisation of connectivity in ephrinA5 conditional knockout mice. Here we showed that target-independent ephrinA/EphA-mediated axon-axon repulsion represents a novel element in retino-collicular mapping (Suetterlin and Drescher; Neuron 84, p740-752 (2014)).

Study of axon guidance and synaptogenesis in the visual system, including development of topographic maps. Focus on EphA/ephrinAs and neurotrophins.

Understanding the role of vesicle transport and autophagy during neural development.

Understanding the molecular mechanisms underlying autism spectrum disorders.