eneurin C-terminal associated peptides (TCAPs) are a novel family of peptides encoded on the last exon of the teneurin genes. The predicted peptide sequences are highly conserved across metazoans and possess the structural hallmarks of a cleavable bioactive peptide that are 40 or 41 amino acid residues. One of the peptides in the family, TCAP-1, is a potent regulator of neurite outgrowth and dendritic spine density in the hippocampus and inhibits corticotropin-releasing factor (CRF)-associated stress-induced and cocaine-seeking behaviours. The effects of TCAP-1 are long lasting, suggesting that TCAP-1 plays a significant role in the regulation of cell-to-cell communication and cellular plasticity. Moreover, TCAP-1 regulates cellular energy, metabolism and cell survival and may, therefore, possess functional attributes outside of the CNS. However, the molecular mechanisms associated with TCAP-1-mediated trophic effects are not known. My research was aimed to 1) determine whether TCAP-1 exerts its effects as part of a direct teneurin-1 function, whereby TCAP-1 represents a functional region of the large teneurin-1 protein, or if it has an independent role, either as a splice variant or post-translational proteolytic cleavage product of teneurin-1; 2) map the distribution of TCAP-1-immunoreactivity and TCAP-1 binding sites in mouse; 3) elucidate the molecular mechanism by which TCAP-1 regulates cytoskeletal dynamics; and 4) investigate a role for TCAP-1 in male reproduction. My research establishes that the C-terminal region of teneurin-1, corresponding to TCAP-1, can be both structurally and functionally independent from teneurin-1 in both the brain and testis of the adult mouse. Furthermore, I provide novel evidence that functionally links the teneurin-TCAP-1 system with the dystroglycan complex and provide new insight into the molecular and signaling mechanisms by which TCAP-1 regulates cytoskeletal dynamics. These studies implicate the teneurins in a broader range of neuroendocrine and trophic functions than previously thought and furthers our understanding of the mechanisms associated with TCAP-1-mediated function in the body.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/43941 |
| Date | 05 March 2014 |
| Creators | Chand, Dhan |
| Contributors | Lovejoy, David |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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