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Title: The mechanisms controlling embryonic axon growth and guidance
Author: Brown, Samantha
ISNI:       0000 0004 7432 0525
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2018
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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.
Supervisor: Erskine, Lynda ; Vargesson, Neil Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pregnancy ; Human embryo ; Axons ; Nervous system