Slits and their Roundabout (Robo) receptors were identified based on their role in regulating axon guidance, but are known to play multiple roles in development, including regulating heart development and myoblast migration. There are 3 vertebrate Slits (Slit1 – 3) and 4 Robos (Robo1 – 4), and previous work has demonstrated expression of Slit and Robo family members in and around developing joints where their function is unclear. Mutations in human Robo3 have been linked to degenerative joint disorders, such as scoliosis and rheumatoid arthritis. Misregulation of other members of the Slit/Robo signalling pathway is also reported in cells from arthritic joints. This suggests that Slit/Robo signalling is required for normal joint development and/or maintenance, though our understanding of their roles in these processes is rudimentary. The central question of my thesis is to determine the role/s of Slit/Robo signalling in limb and joint development. In situ hybridisation confirmed strong expression of Slits and Robos throughout mouse limb and joint development, though no expression of Slit1 or Robo3 was detected. Analysis of Slit1/2, Slit3 and Robo1 mutant (loss-of-function) mice revealed normal limb development, however misexpression of dominant-negative Robo2 during chicken limb development caused shortening of cartilage elements. To begin to identify molecular changes that may compensate for the loss of Slit/Robo signalling I demonstrated members of the Sema3/PlexinA/Nrp axon guidance family are expressed in patterns comparable to those of Robo1, Robo2 and Slit3. I discovered that PlexinA1 is downregulated in Slit3 mutant mouse limbs. My results suggest the role for Silt/Robo signalling may be more complex than previously thought and do not define a clear role for signalling during limb development. My results suggest the role for Silt/Robo signalling may be more complex than previously thought and do not define a clear role for signalling during limb development. Previous work has linked Slit/Robo signalling to development of degenerative joint disorders, and I propose some hypotheses as to how Slit/Robo signalling could cause bone and joint defects.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:701785 |
| Date | January 2016 |
| Creators | Diamond, Alexandra Jane |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=231142 |
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