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The Journal of Neuroscience, December 27, 2006, 26(52):13413-13427; doi:10.1523/JNEUROSCI.3528-06.2006

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Development/Plasticity/Repair
Neuromuscular Development in the Absence of Programmed Cell Death: Phenotypic Alteration of Motoneurons and Muscle

Robert R. Buss,¹ Thomas W. Gould,¹ Jianjun Ma,² Sharon Vinsant,¹ David Prevette,¹ Adam Winseck,¹ Kimberly A. Toops,¹ James A. Hammarback,¹ Thomas L. Smith,² and Ronald W. Oppenheim¹

¹Department of Neurobiology and Anatomy, The Neuroscience Program, and ²Department of Orthopaedic Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Correspondence should be addressed to Ronald W. Oppenheim, Department of Neurobiology and Anatomy, The Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, NC 27157. Email: roppenhm{at}wfubmc.edu

The widespread, massive loss of developing neurons in the central and peripheral nervous system of birds and mammals is generally considered to be an evolutionary adaptation. However, until recently, models for testing both the immediate and long-term consequences of preventing this normal cell loss have not been available. We have taken advantage of several methods for preventing neuronal death in vivo to ask whether rescued neurons [e.g., motoneurons (MNs)] differentiate normally and become functionally incorporated into the nervous system. Although many aspects of MN differentiation occurred normally after the prevention of cell death (including the expression of several motoneuron-specific markers, axon projections into the ventral root and peripheral nerves, ultrastructure, dendritic arborization, and afferent axosomatic synapses), other features of the neuromuscular system (MNs and muscle) were abnormal. The cell bodies and axons of MNs were smaller than normal, many MN axons failed to become myelinated or to form functional synaptic contacts with target muscles, and a subpopulation of rescued cells were transformed from - to -like MNs. Additionally, after the rescue of MNs in myogenin glial cell line-derived neurotrophic factor (MyoGDNF) transgenic mice, myofiber differentiation of extrafusal skeletal muscle was transformed and muscle physiology and motor behaviors were abnormal. In contrast, extrafusal myofiber phenotype, muscle physiology, and (except for muscle strength tests) motor behaviors were all normal after the rescue of MNs by genetic deletion of the proapoptotic gene Bax. However, there was an increase in intrafusal muscle fibers (spindles) in Bax knock-out versus both wild-type and MyoGDNF mice. Together, these data indicate that after the prevention of MN death, the neuromuscular system becomes transformed in novel ways to compensate for the presence of the thousands of excess cells.

Key words: motoneurons; spinal cord; muscle; embryo; cell death; development

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Received Aug. 15, 2006; revised Oct. 27, 2006; accepted Oct. 30, 2006.

Correspondence should be addressed to Ronald W. Oppenheim, Department of Neurobiology and Anatomy, The Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, NC 27157. Email: roppenhm{at}wfubmc.edu

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