The overall objective of this project is to identify the mechanisms that set the position of motor neuron cell bodies, and to control motor axon exit out of the CNS. Motor neurons form early in embryonic development, and their cell bodies cluster in precise positions near the ventral midline, the floor plate. The positioning of motor neuron cell bodies is of fundamental importance for motor input and output. In mouse embryos with mutations in the Robo axon guidance receptors, we discovered that motor neuron cell bodies shift into the floor plate. This shift reveals a surprising ability of motor neuron cell bodies fro all levels of the neuraxis to migrate extensively. The hypothesis to be tested is that motor neuron migration is regulated by two opposing sets of guidance signals from the floor plate: repellent Slit/Robo signals and attractive Netrin/DCC signals. Our model is that these guidance signals have closely balanced effects, trapping motor neurons in specific positions to form motor nuclei, and also guiding their axons out of the CNS. This exploratory application will use a range of approaches including mutant mice and in vitro migration assays for motor neurons to define the basic mechanisms that control their migration.
The aims of the project are to test the function of floor plate guidance signals in controlling motor neuron migration, specifically the opposing Slit repellent and Netrin attractant signals, and to identify the cellular mechanisms that control migration responses to the cues. A related aim will explore the mechanisms of guidance cues in controlling where the motor axons exit the central nervous system. Our experiments will also define a novel function of Slit/Robo signals in a set of cells, the boundary cap, that prevent motor neuron cell bodies from ectopically migrating out along the motor nerve. The outcome of the project will be to develop a new viewpoint of motor neuron differentiation, by defining the mechanisms in which motile motor neuron cell bodies are constrained in static positions by a balance between opposing sets of guidance cues.

Public Health Relevance

Motor neurons form early in brain development as clusters in precise positions in the brain stem and spinal cord. This project will define how two sets of molecular signals are used to set the position of motor neurons, and to determine how these signals also regulate motor axon exit out of the central nervous system.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Riddle, Robert D
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University of Nevada Reno
Schools of Arts and Sciences
United States
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Kim, Minkyung; Fontelonga, Tatiana M; Lee, Clare H et al. (2017) Motor axons are guided to exit points in the spinal cord by Slit and Netrin signals. Dev Biol 432:178-191
Bjorke, Brielle; Shoja-Taheri, Farnaz; Kim, Minkyung et al. (2016) Contralateral migration of oculomotor neurons is regulated by Slit/Robo signaling. Neural Dev 11:18
Moreno-Bravo, Juan A; Martinez-Lopez, Jesus E; Madrigal, M Pilar et al. (2016) Developmental guidance of the retroflex tract at its bending point involves Robo1-Slit2-mediated floor plate repulsion. Brain Struct Funct 221:665-78
Kim, Kyung-Tai; Kim, Namhee; Kim, Hwan-Ki et al. (2016) ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neurons. Sci Rep 6:36491
Lee, Hojae; Kim, Minkyung; Kim, Namhee et al. (2015) Slit and Semaphorin signaling governed by Islet transcription factors positions motor neuron somata within the neural tube. Exp Neurol 269:17-27
Shoja-Taheri, Farnaz; DeMarco, Arielle; Mastick, Grant S (2015) Netrin1-DCC-Mediated Attraction Guides Post-Crossing Commissural Axons in the Hindbrain. J Neurosci 35:11707-18
Kim, Minkyung; Fontelonga, Tatiana; Roesener, Andrew P et al. (2015) Motor neuron cell bodies are actively positioned by Slit/Robo repulsion and Netrin/DCC attraction. Dev Biol 399:68-79
García-Peña, Claudia M; Kim, Minkyung; Frade-Pérez, Daniela et al. (2014) Ascending midbrain dopaminergic axons require descending GAD65 axon fascicles for normal pathfinding. Front Neuroanat 8:43
Wu, Jingwen; Bao, Jianqiang; Kim, Minkyung et al. (2014) Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis. Proc Natl Acad Sci U S A 111:E2851-7
Kim, Minkyung; Farmer, W Todd; Bjorke, Brielle et al. (2014) Pioneer midbrain longitudinal axons navigate using a balance of Netrin attraction and Slit repulsion. Neural Dev 9:17