On a daily basis organisms are confronted with constant sensory input requiring a filtering process of information e.g. necessary for survival or being simply relevant for each individuals personality. To accomplish this vital task elaborate networks of billions of neurons are established in the brain. We wish to understand these processes shaping the assembly of neuronal circuits.

Initially, during nervous system development, single neurons are connected with each other in a highly organised fashion. In first step towards brain wiring neurites growing out from cell bodies differentiate into an axon and multiple dendrites. Especially the axon is navigating long distances (imagine the spinal cord) to bridge its original and final target position. To ensure appropriate target selection, the navigating axon tip (the growth cone) is instructed by guidance cues (e.g. ephrins, semaphorins, slits and netrins) presented in the environment. Activation of axon guidance receptors on the growth cone surface results in a fine-tuned balance between the axon turning towards (growth cone attraction) or away (growth cone repulsion) from the target. In doing so, guidance molecules influence the poly-/depolymerisation status of actin and microtubules thereby allowing for dynamic rearrangements of these cytosceletal filaments. Once the initial set-up of functional neuronal connections has developed, neuronal networks retain the capability of resculpting synaptic contacts throughout life. On that note we employ the hippocampus, a key brain region for learning and memory acquisition, as a preferred model system.

Central to our research is the role of neuronally induced gene expression programs in the nervous system governed by the MADS box transcription factor Serum Response Factor (SRF). SRF was originally identified in the immediate early gene (IEG) response, providing rapid and transient increase of c-Fos mRNA in cells upon e.g. serum stimulation. Meanwhile, besides IEGs, a considerable number of genes coding for the cytosceletal apparatus (like ß-Actin, Vinculin, Zyxin, Gelsolin) have been shown to be regulated by SRF. Thus, SRF is strongly impinging on cytosceletal dynamics and SRF activity in turn is (e.g. by the cofactor MAL) is also adjusted by the G- vs. F-actin equilibrium.

We used conditional mouse Srf mutagenesis to demonstrate a pivotal role of SRF in the assembly of the hippocampal mossy fiber projection. Loss of SRF was accompanied by reduced neurite outgrowth, profound mossy fiber misrouting and aberant synaptic targeting. Guidance cues provided by e.g. ephrins rely on SRF activity in the nucleus: the aberant retention of filamentous actin (and microtubule) rings after ephrin-A induced growth cone collapse suggests that SRF controls actin depolymerisation.

Current projects address how the action of a guidance cue acting locally at the growth cone is orchestrated with gene expression programs exerted in the distant nucleus of a neuron. We are particularly interested in deciphering signalling cascades initiated in the growth cone which are transmitted through the neurite and eventually lead to a SRF mediated transcriptional response. Using genomic and proteomic approaches we analyse established and novel brain specific SRF target genes faithfully ensuing SRF‘s function in neurite outgrowth and axonal guidance. These findings will likely broaden our understanding on SRF’s role in cytosceletal scaffold regulation. Given SRF’s ability to strongly stimulate neurite outgrowth we address a putative role of SRF in neuronal regeneration contributing to the promotion of renewed outgrowth of lesioned nerve fibers.