Trans-axonal signaling during developmental and regenerative assembly of peripheral nerves and neuromuscular circuitry
Final Report Abstract
The project globally aimed at resolving cell surface-based mechanisms driving peripheral nerve assembly as a simplified model for understanding how vast numbers of axons become arranged within the white matter tracts of the developing brain. This involved resolving the developmental timing, nature and significance of axon type-dependent interactions and their contribution to peripheral nerve assembly (aim 2.1), studying the contribution of neuromuscular-disease linked VAPB/ALS8 as a potential non-canonical interaction partner of EphA receptor tyrosine kinases to trans-axon signaling and peripheral nerve assembly (aim 2.2) and the identification and targeted manipulation of trans-axonal signaling mechanisms influencing regenerative peripheral nerve assembly (aim 2.3). To briefly summarize, aim 2.1 has been successfully concluded by uncovering a phylogenetically conserved network of axon-type interactions driving vertebrate peripheral nerve assembly, thus laying the groundwork for studying their molecular underpinnings. The working hypothesis for aim 2.2 had to be revised because, at least in the biological context studied by us, VAPB/ALS8 could not be verified as an interaction partner for EphAs. The search for the “missing” EphA interaction partner/s involved in sensory and motor axon segregation during peripheral nerve assembly is therefore continuing, an endeavor that is greatly aided by the success of “aim 2.1”. Aim 2.3 led to a new and unexpected avenue of research that is still ongoing because, instead of axonal factors influencing peripheral nerve regeneration, we identified a glia-derived signal contributing to the fidelity of axon regeneration and the maintenance of peripheral nerve integrity linked to the development of nerve injurytriggered chronic pain, the study of which required some methodological adjustments to our original approach.
Publications
- What axons tell each other: axon-axon signaling in nerve and circuit assembly. Current Opinions in Neurobiology 23: 974-982, 2013
Wang, L., and Marquardt, T.
(See online at https://dx.doi.org/10.1016/j.conb.2013.08.004) - A conserved axon-type hierarchy governing peripheral nerve assembly. Development 141: 1875-1883, 2014
Wang L, Mongera A, Bonanomi D, Cyganek L, Pfaff SL, Nüsslein-Volhard N, Marquardt T
(See online at https://doi.org/10.1242/dev.106211) - Dlk1 promotes a fast motor neuron biophysical signature required for peak-force execution. Science 343: 1264- 1266, 2014
Müller D, Cherukuri P, Henningfeld K, Poh CP, Wittler L, Grote P, Schlüter O, Schmidt J, Laborda J, Bauer SR, Brownstone RM, Marquardt T
(See online at https://doi.org/10.1126/science.1246448)
