Generation and Analysis of Motor Neuron Disease Models in Zebrafish
| Main Author: | |
|---|---|
| Language: | English |
| Published: |
The Ohio State University / OhioLINK
2012
|
| Subjects: | |
| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1337276861 |
| id |
ndltd-OhioLink-oai-etd.ohiolink.edu-osu1337276861 |
|---|---|
| record_format |
oai_dc |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biomedical Research Molecular Biology Neurosciences motor neuron zebrafish ALS SOD1 SMA SMN plastin 3 |
| spellingShingle |
Biomedical Research Molecular Biology Neurosciences motor neuron zebrafish ALS SOD1 SMA SMN plastin 3 Lyon, Alison Nicole Generation and Analysis of Motor Neuron Disease Models in Zebrafish |
| author |
Lyon, Alison Nicole |
| author_facet |
Lyon, Alison Nicole |
| author_sort |
Lyon, Alison Nicole |
| title |
Generation and Analysis of Motor Neuron Disease Models in Zebrafish |
| title_short |
Generation and Analysis of Motor Neuron Disease Models in Zebrafish |
| title_full |
Generation and Analysis of Motor Neuron Disease Models in Zebrafish |
| title_fullStr |
Generation and Analysis of Motor Neuron Disease Models in Zebrafish |
| title_full_unstemmed |
Generation and Analysis of Motor Neuron Disease Models in Zebrafish |
| title_sort |
generation and analysis of motor neuron disease models in zebrafish |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2012 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1337276861 |
| work_keys_str_mv |
AT lyonalisonnicole generationandanalysisofmotorneurondiseasemodelsinzebrafish |
| _version_ |
1719430605993672704 |
| spelling |
ndltd-OhioLink-oai-etd.ohiolink.edu-osu13372768612021-08-03T06:05:02Z Generation and Analysis of Motor Neuron Disease Models in Zebrafish Lyon, Alison Nicole Biomedical Research Molecular Biology Neurosciences motor neuron zebrafish ALS SOD1 SMA SMN plastin 3 <p>Motor neuron diseases are characterized by a loss of motor neurons (MNs) in the spinal cord, and progressive muscle weakness dues to compromised synapses at the neuromuscular junction (NMJ). In diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), the loss of MNs results in paralysis and premature death. Genetic causes have been identified for both diseases. Mutations in numerous genes, including superoxide dismutase-1 (SOD1), have been identified as causes of ALS; whereas SMA is caused by low levels of survival motor neuron protein (SMN). The majority of identified genes affected in both of these diseases seem to have a nearly ubiquitous pattern of expression. In order to understand why motor neurons die in these diseases, the molecular mechanisms that result from these genetic abnormalities must be understood. Although these genes are linked to motor neuron diseases, it is unclear how they affect motor neuron function and survival.</p> <p>Zebrafish are small vertebrates with a simplified nervous system, are translucent during development, can provide large numbers of embryos and are suitable for large-scale drug screening. To study mechanisms of Sod1 using zebrafish, we generated and characterized transgenic mutant <i>sod1</i> models of ALS. These fish displayed characteristic hallmark phenotypes of disease, including altered neuromuscular junctions (NMJs), reduced swimming time in an endurance test, motor neuron loss, paralysis, and reduced survival. Initially, mutant Sod1, but not wild-type Sod1 fish induced <i>hsp70</i> promoter-driven DsRed expression in neuronal tissues without being exposed to heat stress. However, this response became variable over time, and wild-type Sod1 fish began expressing <i>hsp70</i>:DsRed in various tissues as well in unpredictable patterns. While this response is not a suitable candidate for drug screening, it raises the possibility of developing a transgenic fish with a fluorescent maker of cellular stress. In order to identify possible candidate genes in order to generate such a fish, early molecular events and pathways that are affected by mutant Sod1 expression must first be identified. At that point, candidate genes could be tested for drug screening.</p><p>To elucidate how low levels of SMN cause motor neuron dysfunction, we examined plastin 3 rescue of motor axon defects in <i>smn</i> morphant zebrafish embryos. Plastin 3 is an actin bundling protein that regulates actin dynamics in multiple cell types. In developing neurons, actin dynamics are particularly important for the movement of the growth cone at the end of the axon. We reasoned that plastin 3 was rescuing defects in <i>smn</i> morphants via modulation of actin dynamics. However, plastin lacking all actin-binding domains was still able to rescue motor axons in <i>smn</i> morphants. Interestingly, the N-terminal EF hand motifs of plastin were required for PLS3 rescue of motor axon defects. Additionally, other actin-modifying proteins were unable to substitute for PLS3 in <i>smn</i> morphant axon rescue suggesting this protein has a unique function in motor axon outgrowth. Further work will be needed to determine how the EF hands of PLS3 function in these embryos.</p><p>Both diseases will benefit from a mechanistic understanding of the molecular pathways necessary for normal motor neuron development and how their alteration leads to disease pathology. Hopefully, this understanding will ultimately lead towards successful treatments of these diseases.</p> 2012-06-22 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1337276861 http://rave.ohiolink.edu/etdc/view?acc_num=osu1337276861 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |