dc.contributor.advisor | Broadie, Kendal | |
dc.creator | Leahy, Shannon Nicole | |
dc.date.accessioned | 2024-08-15T15:46:09Z | |
dc.date.available | 2024-08-15T15:46:09Z | |
dc.date.created | 2024-08 | |
dc.date.issued | 2024-05-15 | |
dc.date.submitted | August 2024 | |
dc.identifier.uri | http://hdl.handle.net/1803/19144 | |
dc.description.abstract | Cytoplasmic protein tyrosine phosphatase non-receptor type 11 (PTPN11) and Drosophila homolog Corkscrew (Csw) regulate the mitogen-activated protein kinase (MAPK) pathway via a conserved autoinhibitory mechanism. Disease causing loss-of-function (LoF) and gain-of-function (GoF) mutations both disrupt this autoinhibition to potentiate MAPK signaling. At the Drosophila neuromuscular junction (NMJ) synapse, LoF/GoF mutations elevate transmission strength and reduce activity-dependent (AD) synaptic depression. Fragile X Mental Retardation Protein (FMRP) binds csw mRNA and neuronal Csw protein is elevated in Drosophila fragile X mental retardation 1 (dfmr1) nulls. Trans-heterozygous csw/+; dfmr1/+ recapitulate elevated presynaptic pERK activation and function. In LoF/GoF mutations, the synaptic vesicles (SV) colocalized Synapsin phosphoprotein is highly elevated at rest, but quickly reduced with stimulation, suggesting a larger SV reserve pool with greatly heightened activity-dependent recruitment. Transmission electron microscopy of mutants reveals an elevated number of SVs clustered at the presynaptic active zones, suggesting that the increased SV availability is causative for the elevated neurotransmission. Thus, a FMRP and PTPN11 MAPK/ERK regulative mechanism controls basal and AD neurotransmission strength. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dc.subject | Drosophila | |
dc.subject | Fragile X Syndrome | |
dc.subject | Noonan Syndrome | |
dc.subject | Noonan Syndrome Multiple Lentigines | |
dc.subject | Corkscrew | |
dc.subject | PTPN11 | |
dc.subject | FMRP | |
dc.subject | Neuromuscular Junction | |
dc.title | Genetic and Molecular Dissection of the Corkscrew Phosphatase in Synaptic Function and Neurological Disease | |
dc.type | Thesis | |
dc.date.updated | 2024-08-15T15:46:10Z | |
dc.type.material | text | |
thesis.degree.name | PhD | |
thesis.degree.level | Doctoral | |
thesis.degree.discipline | Biological Sciences | |
thesis.degree.grantor | Vanderbilt University Graduate School | |
dc.creator.orcid | 0000-0002-2987-6191 | |
dc.contributor.committeeChair | McMahon, Douglas | |