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

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).

MicroRNAs, immune cells and pregnancy

“…These include fetal weight restriction and low fetal birth weight (intrauterine growth retardation or IUGR), [81][82][83][84] toxin exposures such as environmental toxins, 85,86 cancer (hepatocellular carcinoma), 87 diabetes mellitus 88 and, the most heavily studied, human pre-eclampsia. 79,[89][90][91][92][93][94][95][96] Many of the pre-eclampsia studies have investigated miRNA expression using high throughput microarray, and qPCR (primarily in order to validate specific microarray findings). Previous studies have established that oxygen tension is implicated in placental development in humans and mice.…”

“…Previous studies have established that oxygen tension is implicated in placental development in humans and mice. 89,90,[97][98][99] Traditionally, hypoxia inducible factor-alpha (HIF-1a) has been associated with regulation of placental cell differentiation in vivo. 90,97 In addition to HIF-1a, the heme oxygenase family has been found to have a direct dependence on oxygen availability, as well as in the downregulation of several crucial genes involved in angiogenesis.…”

“…89,90,[97][98][99] Traditionally, hypoxia inducible factor-alpha (HIF-1a) has been associated with regulation of placental cell differentiation in vivo. 90,97 In addition to HIF-1a, the heme oxygenase family has been found to have a direct dependence on oxygen availability, as well as in the downregulation of several crucial genes involved in angiogenesis. 98 Recent studies have outlined how miR-210 is specifically implicated in pre-eclampsia, a condition of systemic endothelial inflammation that occurs after mid-pregnancy in humans.…”

NK cells, hypoxia and trophoblast cell differentiation

“…23,24 TS cell exposure to a range of oxygen tensions can differentially influence cell proliferation and differentiation. 14,[25][26][27] The impact of oxygen tension on development of invasive trophoblast lineages from TS cell populations has received little attention. Low oxygen tensions can promote differentiation of TS cells toward junctional zone trophoblast cell lineages.…”

“…15 NK cell immunodepletion in the rat results in striking changes in the uterine spiral arteries, these hypoxia-stimulated actions are mediated by the transcription factor complex, hypoxia-inducible factor (HIF). 14,25 HIFs are basic helix loop helix Per-Arnt/AhRSim (bHLH-PAS) transcription factors. 28 Disruption of HIF signaling impairs TS cell responses to low oxygen and acquisition of an invasive phenotype.…”