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Title: The formation and function of putative IgLON cis heterodimeric complexes
Author: McNamee, Christine Jane
ISNI:       0000 0004 2670 4188
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2008
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During development individual neurons have to reach specific locations in the embryo to form a connected nervous system. Molecular complexes form between receptors expressed on the surface of the developing axon and molecular guidance cues in the extracellular environment, to guide the neuron to the correct location. Synapses then connect the axons with their target location. This thesis describes the interactions between the IgLON family of cell adhesion molecules and how these interactions affect their function during neuronal development. There are four members of the IgLON family in chick, namely LAMP, OBCAM, CEPU-I and Neurotractin. They are highly glycosylated proteins, predominantly anchored by a GPI anchor to the extracellular surface of the cell membrane. Initially, the comparative strengths of homophilic and heterophilic trans interactions of CEPU-I, OBCAM and LAMP were established. Generally trans heterophilic interactions within the family have a higher affinity than homophilic interactions, LAMP having the highest heterophilic affinity for CEPU and OBCAM. The lowest affinity of all the trans interactions tested was the LAMP homophilic interaction. Data is presented to suggest IgLONs also interact in cis to form heterodimeric complexes or Diglons. These putative Diglons affect the trans binding affinity for IgLON-FC recombinant proteins, possibly due to a conformational change altering the availability of the IgLON binding site. Biochemical and imaging studies provided additional physical evidence for the Diglon complex. Inhibition of the initiation of neurite outgrowth from chick forebrain neurons was found to be dependent on the presence of two IgLONs in the extracellular environment to suggest formation of putative Diglon heterodimeric complexes facilitates IgLONs to function as negative axon guidance cues. IgLONs have no cytoplasmic domain so are reliant on being part of a molecular complex on the surface of the cell membrane for signal transduction. Assays measuring neurite outgrowth from chick forebrain neurons suggested signal transduction for Diglons is linked to trimeric Go/i membrane proteins and/or to Rho GTPases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral