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The Journal of Neuroscience, May 15, 2002, 22(10):3953-3962

Glial Cell Line-Derived Neurotrophic Factor Promotes the Survival of Early Postnatal Spinal Motor Neurons in the Lateral and Medial Motor Columns in Slice Culture

Wojtek P. Rakowicz^{1, 2, 5}, Christopher S. Staples², Jeffrey Milbrandt³, Janice E. Brunstrom^{1, 2}, and Eugene M. Johnson Jr^{1, 4}

Departments of ¹ Neurology, ² Cell Biology and Physiology, ³ Pathology and Internal Medicine, and ⁴ Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and ⁵ Department of Neurology, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom

The mechanisms by which trophic factors bring about spinal motor neuron (MN) survival and regulate their number during development are not well understood. We have developed an organotypic slice culture model for the in vitro study of the trophic requirements and cell death pathways in MNs of postnatal day 1-2 mice. Both lateral motor column (LMC) and medial motor column (MMC) neurons died within 72 hr when grown in serum-free medium without trophic factors. Brain-derived neurotrophic factor, ciliary neurotrophic factor, and 8-(4-chlorophenylthio)-cAMP promoted the survival of a proportion of the neurons, but glial cell line-derived neurotrophic factor (GDNF) was the most effective trophic factor, supporting ~60% of MNs for 1 week in culture. Homozygous deficiency for bax, a proapoptotic member of the Bcl-2 family, saved the same proportion of neurons as GDNF, suggesting that GDNF alone was sufficient to maintain all "rescuable" MNs for at least 1 week. Analysis of MN survival in GFR-1^/ mice demonstrated that the trophic effect of GDNF was completely mediated by its preferred coreceptor, GDNF family receptor -1 (GFR-1). None of the other GDNF family ligands supported significant MN survival, suggesting that there is little ligand-coreceptor cross talk within the slice preparation. Although MN subtypes can be clearly defined by both anatomical distribution and ontogenetic specification, the pattern of trophic factor responsiveness of neurons from the MMC was indistinguishable from that seen in the LMC. Thus, in contrast to all other factors and drugs studied to date, GDNF is likely to be a critical trophic agent for all early postnatal MN populations.

Key words: subpopulation; trophic factor; apoptosis; neuronal death; Bax; organotypic

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22103953-10$05.00/0

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