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dc.contributor.advisorSegal, Rosalinden_US
dc.contributor.authorWertz, Mary Heleneen_US
dc.date.accessioned2015-07-17T16:29:42Z
dash.embargo.terms2016-05-01en_US
dc.date.created2015-05en_US
dc.date.issued2015-05-18en_US
dc.date.submitted2015en_US
dc.identifier.citationWertz, Mary Helene. 2015. Aberrant microRNA Expression in Spinal Muscular Atrophy Motor Neurons. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17464519
dc.description.abstractSpinal Muscular Atrophy (SMA) is a devastating autosomal-recessive pediatric neurodegenerative disease characterized by loss of spinal motor neurons. It is caused by mutation in the survival of motor neuron 1, SMN1, gene and leads to loss of function of the full-length SMN protein. SMN has a number of functions related to RNA processing in neurons, including RNA trafficking in neurites, and RNA splicing and snRNP biogenesis in the nucleus. While previous work has focused on the alternative splicing and expression of traditional mRNAs, our lab has focused on the contribution of another RNA species, microRNAs (miRNAs), to the SMA phenotype. miRNAs are ~22 nucleotide small RNAs that are involved in post-transcriptional regulation of gene expression. They function by translational repression or mRNA decay of target RNAs. Interestingly, dysregulation of RNA processing and miRNA expression has been identified in motor neuron diseases including SMA and Amyotrophic Lateral Sclerosis. Our lab previously discovered a miRNA, miR-183, that is dysregulated in SMA and impacts its targets in cortical neurons and SMA mouse spinal cords. However, spinal motor neurons are the cell type most affected by SMN loss. We hypothesized that motor neuron specific miRNA changes are involved selective vulnerability in SMA. Therefore, we sought to determine the effect of loss of SMN on spinal motor neurons. To accomplish this, I used microarray and RNAseq to profile both miRNA and mRNA expression in primary spinal motor neurons after acute SMN knockdown. By integrating the miRNA:mRNA profiles we identified dysregulated miRNAs with enrichment in differentially expressed putative targets. miR-431 was the most substantially increased miRNA and a number of its putative targets were downregulated after SMN loss. Further, I confirm that miR-431 directly regulates its target chondrolectin and impacts neurite length. This work is critical to understanding the cell-type specific effect of aberrant miRNA expression in SMN knockdown motor neurons. It demonstrates the contribution of dysregulated RNA processing in motor neurons to neurodegeneration. Furthermore, this work highlights the impact of non-coding RNAs in human disease and points to specific miRNA whose dysregulation potentially impacts motor neuron health.en_US
dc.description.sponsorshipMedical Sciencesen_US
dc.format.mimetypeapplication/pdfen_US
dc.language.isoenen_US
dash.licenseLAAen_US
dc.subjectBiology, Neuroscienceen_US
dc.titleAberrant microRNA Expression in Spinal Muscular Atrophy Motor Neuronsen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorWertz, Mary Heleneen_US
dc.date.available2016-05-02T07:31:23Z
thesis.degree.date2015en_US
thesis.degree.grantorGraduate School of Arts & Sciencesen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
dc.contributor.committeeMemberHart, Anneen_US
dc.contributor.committeeMemberGray, Jesseen_US
dc.contributor.committeeMemberCrickmore, Michaelen_US
dc.type.materialtexten_US
thesis.degree.departmentMedical Sciencesen_US
dash.identifier.vireohttp://etds.lib.harvard.edu/gsas/admin/view/338en_US
dc.description.keywordsmicroRNA, Spinal Muscular Atrophy, motor neuronsen_US
dash.author.emailmary.wertz@gmail.comen_US
dash.identifier.drsurn-3:HUL.DRS.OBJECT:25164049en_US
dash.contributor.affiliatedWertz, Mary H


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