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Genetic and epigenetic mechanisms contribute to motor neuron pathfinding

Nature volume 406, pages 515–519 (2000)Cite this article

Abstract

Many lines of evidence indicate that genetically distinct subtypes of motor neurons are specified during development1, with each type having characteristic properties of axon guidance and cell-body migration2. Motor neuron subtypes express unique combinations of LIM-type homeodomain factors that may act as intrinsic genetic regulators of the cytoskeletal events that mediate cell migration, axon navigation or both3,4,5,6,7. Although experimentally displaced motor neurons can pioneer new routes to their targets8,9,10,11, in many cases the axons of motor neurons in complete isolation from their normal territories passively follow stereotypical pathways dictated by the environment12,13,14,15,16. To investigate the nonspecific versus genetically controlled regulation of motor connectivity we forced all motor neurons to express ectopically a LIM gene combination appropriate for the subgroup that innervates axial muscles. Here we show that this genetic alteration is sufficient to convert the cell body settling pattern, gene-expression profile and axonal projections of all motor neurons to that of the axial subclass. Nevertheless, elevated occupancy of the axial pathway can override their genetic program, causing some axons to project to alternative targets.

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Figure 1: Summary of thoracic motor columns.
Figure 2: Method for ectopic gene expression in embryonic motor neurons.
Figure 3: Ectopic Lhx3 induces MMCm markers in motor neurons.
Figure 4: Analysis of motor neuron settling patterns.
Figure 5: Orthograde fills reveal increased axial projections in TgH Lhx3 ON embryos.
Figure 6: MMCm cell number influences pathfinding.

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Acknowledgements

We thank A. Joyner and A. Auerbach for the training to generate chimaeric embryos; M. McLean for help with immunocytochemistry; S. O'Gorman for Cre mice and the lox–neo–lox cassette; B. Hogan for Lhx1; H. Westphal for Lhx3; L. Jurata, C. Lance-Jones, G. Lemke and J. Thomas; and J. Thaler for insightful comments on the manuscript. This work derives from initial studies on LIM genes while S.L.P. was a fellow with T. Jessell. The Human Frontiers Science Program provided postdoctoral support for K. S., and the National Institutes of Health provided training support for A.E.L. This research was funded by the National Institutes of Health. S.L.P. is a Basil O'Connor, McKnight, Pew, and Alfred P. Sloan Scholar.

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  1. Kamal Sharma

    Present address: Department of Neurobiology, University of Chicago, Chicago, Illinois, 60637, USA

Authors and Affiliations

  1. Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Ann E. Leonard, Karen Lettieri & Samuel L. Pfaff

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  1. Correspondence and requests for materials should be addressed to S.L.P..

    • Samuel L. Pfaff
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Sharma, K., Leonard, A., Lettieri, K. et al. Genetic and epigenetic mechanisms contribute to motor neuron pathfinding . Nature 406, 515–519 (2000). https://doi.org/10.1038/35020078

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