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My thesis investigated the mechanisms important for the development of the mammalian optic pathway and whether Primodos, a hormonal pregnancy test drug used between 1958 and 1978, has the potential to cause birth defects. I found that DSCAM (Down's syndrome cell adhesion molecule) is required for the fasciculation and growth of RGC axons. In mice carrying spontaneous mutations in DSCAM (Dscamdel17) normal axon pathfinding occurs. However, growth of axons from the optic chiasm towards their targets is impaired and axon organisation in the optic chiasm and tracts, and RGC growth cone morphologies, are also altered. Conversely, DSCAM gain-of-function resulted in exuberant growth into the dorsal thalamus. In vitro, DSCAM promotes RGC axon growth and fasciculation independently of cell contact. Along with previous work in the lab, my findings identified DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons. Spondins and their LRP binding partners are expressed in both the retina and around the developing optic pathway, consistent with a role in regulating growth of RGC axons towards visual targets. In vitro retinal explant cultures exposed to cells transfected with F-spondin, or its TSR domains, did not however provide evidence of axon growth modulation via F-spondin. I used Zebrafish embryos, a human cell-line and mouse retinal explants to investigate the actions of the components of Primodos upon embryonic axon growth, intersomitic vessel development and changes to cell number, proliferation and cell death. NA/EE-mixture exposure caused rapid morphological damage in Zebrafish embryos, affecting multiple organ systems and affecting physical movement. The NA/EE-mixture also affects nerve outgrowth and blood vessel patterning directly and accumulates in the III developing embryo for at least 24 hours. These data demonstrate that Norethisterone acetate and Ethinyl estradiol are potentially teratogenic, depending on dose applied and embryonic stage of development.

The following dissertation herein discusses the role of axonal protein synthesis in Aβ1-42-dependent neurodegeneration, which has important implications in AD pathogenesis. In Part 1, I provide a brief introduction to relevant topics including neurodegeneration and axonal protein synthesis. In Part 2, I discuss findings that we published in 2014 describing a mechanism by which axonal exposure to Aβ1-42 induces cell death via axonal synthesis and retrograde transport of a transcription factor, ATF4. In Part 3, I discuss a follow-up project that I conducted independently, which is not yet published but is in preparation for submission describing the immediate effect of Aβ1-42 on axonal protein synthesis, which mediates the downstream axonal ATF4 signaling events described in Part 2. In Part 4, I discuss the key findings from these two projects including their significance and potential future directions. In the Appendix, I provide details regarding experimental methods and statistical analyses performed in Part 3.

During neural development, axons rely on extracellular cues to reach their target regions. Although extracellular signaling is one of the principal determinants for the growth of developing axons, only a small handful of known signaling cues has been identified. The existence of some 86 billion neurons of different subtypes, which ultimately form numerous functional circuits in the human nervous system, means an enormous number of extracellular cues would be required during development. Current views hold that even if more extracellular cues were to be discovered, they would never number large enough to account for the complexity of the human nervous system. Rather, intracellular signaling pathways and other cell-intrinsic mechanisms expand the ways in which a neuron can respond to extracellular cues by tuning the degree of responsiveness to them. Cell-intrinsic signaling pathways also give axons the ability to actively control their own development. These pathways can operate independently of the extracellular environment or even independently of the cell body, where the majority of protein synthesis takes place. For example, the local translation of proteins in the axon gives it autonomous control to immediately respond to changing demands in the environment. Local translation also occurs in other cell types, but the compartmentalized control over growth is especially important for neurons since the axon can extend up to a meter away from the cell body. In addition to local translation, axonally derived transcription factors, which can be locally synthesized in or localized to the axon, provide another means to control axon development. Axonally derived transcription factors act as physiological sensors and relay information about events happening in the periphery back to the cell body in order to effectuate a global response. It has recently been shown that transcription factors belonging to the OASIS family are activated by proteolysis in axons. Following their activation by proteolytic cleavage, the transcriptionally active N-terminus of these factors is transported to the cell body to activate global transcriptional pathways. For at least one OASIS family member, CREB3L2, this cleavage event simultaneously produces the C-terminus, which is capable of undergoing secretion. The secreted C-terminus of CREB3L2 acts as an accessory ligand for the activation of Hh pathways in chondrocytes. The generation of two bioactive proteins from one transcription factor, a transcriptionally active portion and a secreted portion, raised the question of whether there was a local function for OASIS transcription factors in axons. Through my research, I identified a mechanism in which DRG axons secrete the C-terminus of CREB3L2, which promotes axon growth in a paracrine manner. CREB3L2 is a transcription factor whose translation is induced by physiological ER stress. For CREB3L2 to be active, it must be cleaved by S2P, which I found is expressed in developing axons. Following proteolysis of CREB3L2 by S2P, the secreted C-terminus of CREB3L2 promotes the formation of Shh and Ptch1 complexes along axons. I found that upon depletion of the secreted CREB3L2 C-terminus, binding of Shh to the Ptch1 receptor is diminished. Returning the CREB3L2 C-terminus to the cultures exogenously was sufficient to rescue the formation of these complexes. These results highlight an intrinsic role for Shh signaling in developing DRG axons. Moreover, these results demonstrate how ER stress machinery is recruited to axons and promotes axon outgrowth. Finally, these results illustrate a novel, neuron-intrinsic mechanism by which developing axons actively regulate their own growth.

Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2007 May 24

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Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references. Also available in print.

Thesis (Ph.D.)--University of Delaware, 2008. / Principal faculty advisor: Jeffery L. Twiss, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (M.S.)--University of Nevada, Reno, 2008. / "August, 2008." Includes bibliographical references (leaves 20-23). Online version available on the World Wide Web.