Trans-axonal signaling during developmental and regenerative assembly of peripheral nerves and neuromuscular circuitry

• Applicant: Professor Dr. Till Marquardt
• Subject Area: Developmental Neurobiology
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 227585579

Peripheral nerves (PNs) comprise neural pathways facilitating efferent control over movement apparatus and organ function, and afferent pathways underlying somatosensation. The developmental or regenerative assembly of PNs entails orderly integration of the different axon types into a common principle grid of nerve trajectories, and provides a simplified model for investigating organizing principles that accommodate vast arrays of axon types within the white matter tracks of the CNS. Misalignment of axon types can lead to catastrophic intermingling of functionally disparate pathways, underlying conditions including neuropathic pain. Despite the central importance for the parallel establishment of neuromuscular, somatosensory and sympathetic circuitries, the coordinating principles that integrate different axon types into tightly aligned yet functionally segregated PN pathways remain poorly understood. The proposal will investigate cell surface-based mechanisms driving PN assembly through targeted gene and cell-lineage manipulation in mouse and chick, combined with circuit tracing, electrophysiology and live-cell microscopy. This entails dissecting dynamic processes driving trans-axon interactions, and their contribution to the developmental and regenerative assembly of PNs, and their corresponding circuitries, at the anatomical and functional level. Based on an extensive body of previous and preliminary work by my group, the proposal will tackle the following questions: (i) what is the physiological contribution of the neuromuscular-disease linked VAPB/ALS8 protein to the assembly of neuromuscular circuits? (ii) To what degree does VAPB/ALS8 as a newly identified interaction partner of EphA receptor tyrosine kinases contribute to trans-axon signaling and formation of functional sensory-motor circuits? (iii) Will VAPB/ALS8ýEphA/ephrin-A crosstalk play a role during regenerative PN assembly? (iv) Could the targeted manipulation of trans-axonal signaling mechanisms be exploited to influence precision and efficacy of developmental or regenerative PN assembly?

• DFG Programme: Research Grants