Direct protein–protein interaction between the intracellular domain of TRA-2 and the transcription factor TRA-1A modulates feminizing activity in <i>C. elegans</i>

It is established that O(2) levels regulate cell fate determination in vivo and that HIF is essential for mammalian placentation and that hypoxia promotes the in vitro differentiation of trophoblast stem cells into spongiotrophoblasts as opposed to giant cells.

Abstract

In the nematode Caenorhabditis elegans, the zinc finger transcriptional regulator TRA-1A directs XX somatic cells to adopt female fates. The membrane protein TRA-2A indirectly activates TRA-1A by binding and inhibiting a masculinizing protein, FEM-3. Here we report that a part of the intracellular domain of TRA-2A, distinct from the FEM-3 binding region, directly binds TRA-1A. Overproduction of this TRA-1A-binding region has tra-1-dependent feminizing activity in somatic tissues, indicating that the interaction enhances TRA-1A activity. Consistent with this hypothesis, we show that tra-2(mx) mutations, which weakly masculinize somatic tissues, disrupt the TRA-2/TRA-1A interaction. Paradoxically, tra-2(mx) mutations feminize the XX germ line, as do tra-1 mutations mapping to the TRA-2 binding domain. We propose that these mutations render tra-2 insensitive to a negative regulator in the XX germ line, and we speculate that this regulator targets the TRA-2/TRA-1 complex. The intracellular domain of TRA-2A is likely to be produced as a soluble protein in vivo through proteolytic cleavage of TRA-2A or through translation of an XX germ line-specific mRNA. We further show that tagged derivatives of the intracellular domain of TRA-2 localize to the nucleus, supporting the hypothesis that this domain is capable of modulating TRA-1A activity in a manner reminiscent of Notch and Su(H).