Signalling by Teuneurin-1

The work described in this thesis focuses on one member of the teneurin family: teneurin-1 (ten-1). The chicken ten-1 gene encodes a 300kDa protein. The intracellular domain of ten-1 harbours proline rich sequences, which serve as docking sites for SH3-domain containing proteins, followed by a transmembrane domain, an extracellular domain containing several EGF-like repeats involved in protein dimerization and 26 YD repeats.
Regulated Intramembrane Proteolysis (RIP) initiates an event that involves the cleavage of type I and II transmembrane proteins, leading to the translocation of the cleaved intracellular domain into the nucleus to regulate transcription of target genes. Prominent proteins known to be activated through RIP are Notch, Amyloid Precursor Protein (APP), Sterol regulatory element-binding protein (SREBP) and others. Recently, evidence of a cleavage mechanism of this type has also been obtained for the teneurin family of proteins.
With the aim to identify binding partners of teneurin-1, yeast two-hybrid studies were performed. Both CAP/ponsin and MBD1 were found to interact with the intracellular domain of ten1 (IDten-1). In cell fractionation experiments, IDten-1 co-purified with CAP/ponsin and MBD1 in the nuclear matrix of U2OS cells. Moreover, when full-length teneurin-1 was expressed in cells in culture, the generation of IDten-1 could be detected, suggesting that this fragment is the result of an endogenous cleavage mechanism.
Based on these observations, we concluded that IDten-1 either alone, or in a complex with CAP/ponsin and MBD1 could be involved in the regulation of transcription of yet-to-be identified target genes. To identify such target genes the gene expression profile of cells induced to express IDten-1 was compared to control cells not induced to express this domain. This analysis revealed a particular transcript, here defined as XM_039676, the expression of which was highly upregulated in the presence of IDten-1. This gene represents the first candidate for a RIP-induced target gene of ten-1.