Homeobox Gene HLX1 is a Regulator of Colony Stimulating Factor-1 Dependent Trophoblast Cell Proliferation

The cytokine colony stimulating factor-1 (CSF-1) is a key regulator of the proliferation, differentiation and activation of mononuclear phagocytes. CSF-1 also plays an important role in reproduction. CSF-1 is produced in the placenta and activates signal transduction pathways that significantly increase the proliferation of placental trophoblast cells in culture. The target genes activated by CSF-1 mediated signal transduction in the nucleus are not well understood. Here, we use placental trophoblast cells to investigate potential downstream effector genes of CSF-1. HLX1 is a homeobox gene that controls proliferation in embryonic cell types and haematopoietic cell lineages. We have shown HLX1 is expressed in placental trophoblast cells but its functional role in the placenta is unknown. Following CSF-1 stimulation, HLX1 mRNA expression was significantly increased in SGHPL-4 and HTR-8/SVNeo cultured trophoblast cells (p < 0.001, n = 3). siRNA-mediated reduction of HLX1 mRNA levels with four independent oligonucleotides (siRNAs) resulted in significantly decreased cell proliferation in both cell lines (p < 0.001, n = 4). When HLX1 mRNA levels were reduced in the presence of CSF-1 stimulation, proliferation remained significantly decreased (p < 0.001, n = 4) in both the cell lines. We have shown for the first time that a homeobox gene, HLX1, is a downstream effector gene of CSF-1, that HLX1 regulates placental cell proliferation and that CSF-1 acts, at least in part, through HLX1 to control cell proliferation.