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The effect of growth factors on bulbospinal neurite outgrowth in an in vitro embryonic chick model

University of British Columbia

Injury to the spinal cord of higher vertebrates damages motor axons that connect the brain and brainstem with their targets in the spinal cord. Axotomized central nervous system (CNS) neurons often experience degeneration of the distal axon, retraction of the proximal end, and atrophy of the cell body. Injured neurons in the CNS do not experience significant functional regeneration, so spinal cord insult often results in permanently compromised locomotor ability. The capability of a severed axon to re-grow is thought to depend on the interplay between intrinsic and external cues. Regenerative failure in the mature axon is thought to be the result of: a) failure to survive primary and secondary damage, b) glial scarring, c) presence of inhibitory growth substrates that prevent neuronal extension, and d) decreased availability of neurotrophic factors and permissive substrates supporting neuronal process extension. Application of trophic factors to axotomized neurons has been shown to enhance survival and neurite outgrowth. Although brainstem-spinal connections play the pivotal role in motor dysfunction, we still know relatively little about the trophic sensitivity of these populations. The experiments presented in this study will help to elucidate the role trophic molecules play in process extension in brainstem-spinal neuron populations. Using an assay specifically developed to examine the effect of trophic molecules on neuronal process extension, this study explores the response of bulbospinal populations to various trophic factors. Already investigated in our laboratory using these techniques are members of the fibroblast growth factor family, (FGF-1,-2, -5 and -9). Several growth factors were initially examined for potential trophic effects on the projection neurons of the brainstem. Nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) and epidermal growth factor (EGF) did not effect process outgrowth in the bulbospinal neurons of the vestibular complex (vestibulospinal neurons). Brain derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) significantly enhance mean process length in both the vestibulospinal neurons and projection neurons from the raphe nuclei (raphespinal neurons). Neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) require further study to determine their contribution to process elongation. In order to examine the mechanism of trophic factor effects, immunohistochemistry to the cognate receptors for BDNF and IGF-1 was performed. At the developmental stages used in the study, it was determined that receptors for BDNF and IGF-1 were present both on bulbospinal neurons and on surrounding cells with a non-neuronal morphology. It is hoped that this study will contribute to the growing pool of knowledge on spinal cord injury, and may one day play a role in development of a multi-faceted therapy for spinal cord injury.

Thesis/Dissertation

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2009-08-14

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http://hdl.handle.net/2429/12214

Neuroscience

University of British Columbia

UBCV

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