No description available.

No description available.

Thesis (M.S.) in Zoology--University of Maine, 2006. / Includes vita. Includes bibliographical references (leaves 57-65).

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 248-271).

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

No description available.

Thesis (Ph.D.) in Biochemistry and Molecular Biology--University of Maine, 2008. / Includes vita. Includes bibliographical references (leaves 96-117).

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This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Cleft palate affects approximately 1 in 2000 live births resulting in considerable morbidity to affected individuals and their families. Evidence that the p63 gene is mutated in at least seven human developmental syndromes which are each characterised by varying extents of orofacial clefting, coupled to the severe facial dysmorphism displayed by the p63 mutant mouse, highlight the need to elucidate the role of the p63 during normal and aberrant palatogenesis. In mice, secondary palate development closely mirrors that occurring in humans; consequently, the mouse is a pre-eminent model organism for studying palatogenesis. In mice, the palatal shelves initiate from the maxillary processes and grow vertically, lateral to the tongue. The shelves re-orientate and make contact above the tongue. The medial edge epithelia (MEE) of the apposed palatal shelves adhere to form a midline epithelial seam (MES). Subsequent degeneration of the MES allows mesenchymal confluence across the palate, at which point palatogenesis is considered complete. The mechanisms underlying degeneration of the MES remain contentious; however, in vivo studies suggest that cessation of proliferation, induction of apoptosis and periderm migration are essential to ensure removal of the midline seam. The data presented in this thesis uncover a key role for p63 in controlling these aspects of cell behaviour during palatal shelf fusion. Tgfb3-/- mice exhibit cleft palate with maintained expression of p63 in the MEE. This thesis reveals that epistatically lowering the dosage of p63 in Tgfb3-/- mice rescues this fusion defect, facilitating periderm cell migration out of the MEE and subsequent MES degradation. Recent research suggests that p63 orchestrates a cell adhesion network in the palate. In this context, this thesis suggests the importance of p63 down-regulation in the MES in compromising adhesion at the basal-periderm border, thereby allowing periderm cell migration out from the midline and subsequent MES degradation. To test the hypothesis that down-regulation of p63 is essential for palatal fusion, tetracycline-inducible transgenic animals in which ΔNp63α is targeted to the MEE of the developing palate have been engineered. ΔNp63α bi-transgenic mice presented with cleft palate in which the MES failed to degenerate. An observed lack of apoptotic activity in the MEE of ΔNp63α bi-transgenic mice suggested a role for p63-mediated apoptosis during MES degradation. Gene ontology analysis of a complete range of ΔNp63α transcriptional targets which have been identified in the secondary palate by ChIP-seq, lent support to this hypothesis. The data indicate that p63 down-regulation in the MES is essential to ensure complete removal of the MES and implicate p63 as a key regulator of apoptosis during this process; thereby building on work which suggests that cell death is the major fate of the MEE. In addition to dissecting a pathway of fundamental importance in secondary palate development, this research provides insights into ectodermal development more generally and has wider significance for the study of many congenital malformations.