Signaling Mechanisms Driving the Assembly of the Spinal Neuromuscular Circuitry
Final Report Abstract
The Emmy-Noether grant provided crucial support at a critical time in my career that allowed me to develop an independent research program. The program tackled two principle problems of neurobiology using the neuromuscular system of mouse and chick as an experimentally tractable model: how, during development, do vast arrays of neurites extending from different neuron types assemble into the functional architecture of the nervous system (project I), and how do certain types of neurons, once embedded within neural circuitries, acquire distinctive properties that underlie the ability of the nervous system to execute movements and behaviors (project II)? Project I: My team established methods that now allow us to routinely observe interactions between different neurite types in the culture dish or in the context of the organism.The combination of these assays with genetic techniques allowed us to successfully resolve cellular and molecular mechanisms that drive the self-organization of neurites into parallel, yet functionally independent pathways.These findingsprovidekey insights into the organizational principlesunderlying the orderly integration of vast numbers of neurites into peripheral and central white matter tracts: the fundamental communication pathways of the nervous system. Ongoing investigations now address the contribution of these mechanisms to pathological conditions caused by illicit intermingling of functionally distinct neurites, as well as their influence on regenerative assembly of nerve tracts and circuits. Project II: I further started an ambitious research program aiming at identifying elusive mechanisms that drive thefunctional specification and plasticity of motor neurons: specialized nerve cells that connect the nervous system with skeletal muscles. My team established methods allowing us to identify molecular mechanisms determiningmotor neuron functional properties. The diversification of motor neurons based on variations in these properties underlie their abilityto relay electrical activity patterns generated in the nervous system into defined muscle actions and behavioral outputs.These ongoing investigations further address the contribution of these mechanisms to how motor neurons adapt to physical activity or inactivity, as well as their inherent vulnerability towards ageing and disease. The experience, technical solutions and data gathered through the funding period of the Emmy-Noether grant opened a number of novel research avenues that now occupy a large part of my group, in addition to providing the basis for securing additional grant support, including an ERCgrant in 2012, that place these studies on a solid funding basis for the next couple of years.
Publications
- (2008). Segregation of axial sensory and motor pathways through heterotypic trans-axonal signaling. Science 320: 233-236
Gallarda, B., Bonanomi, D., Müller, D., Brown, A., Alaynick, W.A., Lemke, G., Pfaff, S.L, and Marquardt, T.
- (2011). Anatomical coupling of sensory and motor nerve trajectory through axon tracking. Neuron 71: 263-277
Wang, L., Klein, R., Zheng, B., and Marquardt, T.
- (2012). Direct live monitoring of heterotypic axonal interactions in vitro. Nature Protocols 7: 351-363
Wang, L. and Marquardt, T.
(See online at https://doi.org/10.1038/nprot.2011.442) - (2012). Ret is a multifunctional co-receptor that integrates diffusible- and contact-axon guidance signals. Cell 148: 568-582
Bonanomi, D., Chivatakarn, O., Bai, G., Lettieri, K., Abdesselem, H., Marquardt, T., Pierchala, B.A., and Pfaff, S.L.
(See online at https://doi.org/10.1016/j.cell.2012.01.024)
