The intracellular domain of teneurin-2 has a nuclear function and represses zic-1-mediated transcription

Abstract

Teneurin-2, a vertebrate homologue of the Drosophila pairrule gene ten-m/odz, is revealed to be a membrane-bound transcription regulator. In the nucleus, the intracellular domain of teneurin-2 colocalizes with promyelocytic leukemia (PML) protein in nuclear bodies implicated in transcription control. Since Drosophila ten-m acts epistatically to another pair-rule gene opa, we investigated whether gene regulation by the mammalian opa homologue zic-1 was influenced by the intracellular domain of teneurin-2. We found that zic-mediated transcription from the apolipoprotein E promoter was inhibited. Release of the intracellular domain of teneurin-2 could be stimulated by homophilic interaction of the extracellular domain, and the intracellular domain was stabilized by proteasome inhibitors. We have previously shown that teneurin-2 is expressed by neurons belonging to the same functional circuit. Therefore, we hypothesize that homophilic interaction enables neurons to identify their targets and that the release of the intracellular domain of teneurin-2 provides them with a signal to switch their gene expression program from growth towards differentiation once the proper contact has been made.

Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis

“…ODZ2 and CTNND2 exhibit aberrant expression depending on the cell lines; for example, ODZ2 expression was higher in nontumorous tissues than in tumors in four of the seven cases, suggesting a tumor suppressive role. It is important to note that ODZ2 also colocalized with a tumor suppressor protein, PML, in the nucleus (Bagutti et al, 2003). In contrast, CTNND2 expression was much higher in tumors than in nontumorous tissues in three of the seven cases.…”

“…ODZ2 is a human homolog of the drosophila tenascin major (ten-m) gene, an example of a pair-rule gene, that is, every odd-numbered body segment is deleted in ten-m mutant drosophila embryos. In mammals it encodes a transmembrane protein, putatively acting as a transcriptional regulator (Bagutti et al, 2003). BBX is a human homolog of the drosophila bobby sox gene located in a flightless region and encoding a product with transcription factor activity (Maleszka et al, 1998).…”

Emerging roles for zic genes in early development

“…In cell-based assays, the cytoplasmic domain of Teneurin-2 appears to be cleaved in response to signaling. This intracellular domain translocates into the nucleus, where it reduces the transcription activity of Zic1 (Bagutti et al, 2003). It is not known how the intracellular domain of Teneurin-2 modulates the activity of Zic1 or whether Teneurin-2 and Zic1 interact with each other directly.…”

The expression of teneurin-4 in the avian embryo: potential roles in patterning of the limb and nervous system

“…Similar observations have come from vertebrate systems. When the ICD of teneurin-1 (Nunes et al 2005) or teneurin-2 (Bagutti et al 2003) is expressed in vitro it localizes to the cell nucleus, and antibodies to the ICD of avian teneurin-1 label some cell nuclei in a subset of tissues stained by antibodies to the ECD (Kenzelmann et al 2008). When a potential nuclear localization signal in the ICD of teneurin-1 is mutated, the ICD fails to translocate to the nucleus (Kenzelmann et al 2008).…”