Synapses are necessary for a functional nervous system. To form a synapse, a neuron must first extend an axon, then select its proper synaptic target, and finally, a series of adhesion and adaptor molecules must work together to assemble synaptic machinery adjacent to the postsynaptic target. Faulty synapses lead to many neurological disorders, and despite the medical relevance, the genetic mechanisms that control synaptogenesis are incompletely understood. This dissertation characterizes the novel role of two proteins, Collapsin Response Mediator Protein (CRMP) and Tramtrack 69 (Ttk69), in synapse formation.
CRMPs have previously been shown to mediate growth cone collapse during axon outgrowth and are thought to do so by regulating microtubule assembly and polarity. However, the role CRMP plays at the synapse is unknown. We remove CRMP from Drosophila R7 photoreceptor neurons and find that R7s lacking CRMP form ectopic contacts that contain active zones and are apposed to incorrect targets. To our surprise, we found no alterations in microtubule polarity or organization, and instead found evidence that CRMP might regulate the pattern of calcium influx. In live, developing R7 terminals, we found that R7 calcium transients are normally spontaneous and aperiodic. Interestingly, loss of CRMP increases the frequency and amplitude of these calcium transients. Our results suggest a novel mechanism by which CRMP regulates activity-dependent synapse development. And they indicate that the pattern of calcium transients, even when aperiodic, is critical for this process.
The transcription factor, Ttk69, broadly functions in Drosophila cells to inhibit expression of pro-neural genes. However, temporal expression of Ttk69 in R7s is necessary and sufficient to halt R7 axon growth at their final synaptic target layer. R7s and R8 photoreceptors use different but conserved molecular pathways to control both layer selection and tiling, therefore, I am investigating whether ttk69 is similarly required to regulate R8 synaptogenesis. I have found that ttk69 is expressed in R8 photoreceptor neurons and loss of ttk69 from R8s prevents their axons from extending to their final synaptic target layer. Unlike in R7s, Ttk does not function through the TGFβ/Activin pathway in R8s, but likely functions by preventing expression of Netrins repulsive receptor, Unc-5 to control synaptic target selection.
This dissertation includes co-authored material. / 10000-01-01
| Identifer | oai:union.ndltd.org:uoregon.edu/oai:scholarsbank.uoregon.edu:1794/22754 |
| Date | 06 September 2017 |
| Creators | Casper, Sarah |
| Contributors | Herman, Tory |
| Publisher | University of Oregon |
| Source Sets | University of Oregon |
| Language | en_US |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Rights | All Rights Reserved. |
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