Abstract

The overall goal of our research is to dissect developmental mechanisms that control the formation of specific neuronal circuits. We are using genetic, cell biological, biochemical and structural methods to better understand how the molecular specification of synaptic targets is achieved. In much of our work we are taking advantage of the powerful genetic tools available for the model organism Drosophila. However we have recently started to also extend our studies to the analysis of neural circuit formation in vertebrates. Specifically we are using the model organism Xenopus tropicalis and combine biochemical, reverse genetic as well as imaging techniques for a dissection of neural circuit formation.

Concerning the cellular mechanisms of neuronal wiring we are focusing on two developmental processes that are still poorly understood: Axonal branching and central synapse formation/selection. In order to do so we developed new genetic labeling methods to visualize single axons and single pre-synapses within the CNS . These techniques allow us to resolve important steps underlying axon branching and synapse formation. They also allow us to conduct a genetic dissection of the underlying regulatory pathways (Urwyler et al. (2015), Development).

For the investigation of molecular mechanisms we have been focusing on the recognition specificity and signal transduction of membrane receptors of the Immunoglobulin superfamily (Ig-SF). Specifically, we have been studying the function of the Ig-domain containing neuronal receptor “Dscam” in flies. The Drosophila Dscam receptor is closely related to the human protein Down syndrome cell adhesion molecule (DSCAM). Through alternative splicing the Drosophila Dscam gene gives rise to thousands of receptors with diverse ectodomains (18,496) thought to provide homophilic and possibly heterophilic recognition specificity for neuronal wiring (Schmucker et al., (2000), Cell; Sun et al. (2013), EMBO J .)

Recently we discovered that the diversity of Dscam1 isoforms is also utilized cell-intrinsically where it is essential for complex axonal branching of sensory neurons. Genetic and single cell analysis suggest that the qualitative (i.e. structural) differences between isoforms serve as a rheostat to achieve quantitative control of Dscam1 signaling within axonal growth cones (He et al. (2014), Science).

For more information please see recent publications:

Urwyler, O., Izadifar, A., Dascenco, D., Petrovic, M., He H., Ayaz D., Kremer A., Lippens S., Baatsen, P., Guérin, C.J. & Schmucker, D. Investigating CNS synaptogenesis at single-synapse resolution by combining reverse genetics with correlative light and electron microscopy. Development. 2015;142(2):394-405.

He, H., Kise, Y., Izadifar, A., Urwyler, O., Ayaz D., Parthasarthy, A., Yan, B., Erfurth, M.L., 7Dascenco, D. & Schmucker, D. Cell-intrinsic requirement of Dscam1 isoform diversity for axon collateral formation. Science. 2014; 344(6188):1182-6.

Kise, Y. & Schmucker, D. Role of self-avoidance in neuronal wiring. Curr Opin Neurobiol. 2013, 23(6):983-9.

Sun W, You X, Gogol-Döring A, He H, Kise Y, Sohn M, Chen T, Klebes A, Schmucker D, Chen W. Ultra-deep profiling of alternatively spliced Drosophila Dscam isoforms by circularization-assisted multi-segment sequencing. EMBO J . 2013 ;32(14):2029-38.